预处理化疗增强细胞因子诱导的杀伤细胞的抗肿瘤作用及其机制研究
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摘要
[背景与目的]
传统化疗药物的免疫调节作用已逐渐受到人们的重视,特定剂量特定模式的给药方式可通过多种机制重建机体免疫内环境,调变肿瘤细胞免疫原性。将其作为预处理方案联合后续的过继性细胞免疫治疗,可有效动员机体的免疫系统发挥抗肿瘤作用。本研究旨在观察预处理化疗在小鼠动物肿瘤模型(Lewis(?)市癌、CT-26结肠癌、B16黑色素瘤)中对细胞因子诱导的杀伤细胞(cytokine-induced killer cells, CIK cells)的抗肿瘤活性的增强作用,并从机体免疫内环境的调节以及肿瘤细胞免疫原性的调变两方面探讨介导预处理化疗增效作用的机制。
[材料与方法]
1.建立C57BL/6小鼠Lewis肺癌模型,选用紫杉醇(Paclitaxel, PTX)联合顺铂(Cisplatin, DDP)作为预处理方案(TP方案),荷瘤小鼠随机分为六组：对照组(给予生理盐水,Normal Saline, NS)、NS-3-CIK组(NS后3天给予CIK细胞)、NS-7-CIK组(NS后7天给予CIK细胞)、TP组(给予TP方案)、TP-3-CIK组(TP方案预处理后3天联合CIK细胞)及TP-7-CIK组(TP方案预处理后7天联合CIK细胞)。隔日测量肿瘤长短径监测肿瘤体积,观察各组治疗方案对Lewis肿瘤的抑制作用。
2.分别建立BALB/c野生鼠或BALB/c nu/nu裸鼠CT-26结肠癌模型,随机分为四组：NS组(给予NS)、CIK组(给予CIK细胞)、DDP组(给予DDP)、DDP-CIK组(DDP预处理3天后联合CIK细胞)。隔日测量肿瘤长短径监测肿瘤体积,观察各组治疗方案对CT-26结肠癌的抑制作用,并比较联合方案在两种动物模型中的抗肿瘤作用。
3.建立C57BL/6小鼠B16黑色素瘤模型,随机分为四组：NS组(给予NS)、CIK组(给予CIK细胞)、DDP组(给予DDP)、DDP-CIK组(DDP预处理3天后联合CIK细胞)。隔日测量肿瘤长短径监测肿瘤体积,观察各组治疗方案对B16黑色素瘤的抑制作用。
4.利用绿色荧光蛋白(Green Fluorescence Protein, GFP)转基因小鼠制备GFP+CIK细胞,荧光显微镜追踪其体内迁移分布,观察预处理化疗对CIK细胞体内归巢功能的影响。
5.分离Lewis(?)市癌模型及CT-26结肠癌模型中的肿瘤组织,分别行CD3、FoxP3(Forkhead boxP3)、CD31分子免疫组化染色以评估肿瘤组织局灶T淋巴细胞、Treg细胞的浸润情况以及肿瘤微血管密度的变化。
6.流式细胞术观察预处理化疗后荷瘤鼠各组织中内源性T淋巴细胞、树突状细胞(Dendritic cells, DCs)、髓系来源抑制细胞(Myeloid-derived suppressor cells, MDSCs)、调节性T细胞(Regulatory T cells, Treg cells)的动态变化。
7.MTT法筛选化疗药物5-氟尿嘧啶(5-Fluorouracil,5-FU)、DDP、PTX、多西紫杉醇(Docetaxel,DTX)的体外高、中、低毒性浓度,将这些浓度的化疗药物处理人肺腺癌细胞(A549、SPC-A1、SPC-A1/DTX), WST-1法比较肿瘤细胞在化疗药物预处理前后对CIK细胞体外杀伤作用的敏感性。
8.RT-PCR检测肿瘤细胞经化疗药物处理后各时间点免疫原性分子mRNA水平表达的改变：NKG2D配体(Natural killer group 2, member D ligands, NKG2DL)、Fas受体分子、细胞间黏附分子-1 (Intercellular adhesion molecule-1, ICAM-1)、高迁移率族蛋白1 (High-mobility group box-1, HMGB-1)、钙网织蛋白(Calreticulin, CRT)、DNAM分子(DNAX accessory molecule-1)、Clr-b分子(C-type lectin-related molecule b)。
[结果]
1.在C57BL/6小鼠Lewis肺癌模型中,TP预处理化疗后不同时间点给予CIK细胞免疫治疗均能明显抑制(?)Lewis肺癌的生长(P<0.05),且两时间点间无统计学差异；而单独CIK免疫治疗或TP化疗均不能抑制Lewis肿瘤的生长(P>0.05)。实验结束时两联合治疗组肿瘤体积分别为3377.82±1603.43mm3 (TP-3-CIK组),3183.38±806.08mm3 (TP-7-CIK组);单独CIK治疗组及TP化疗组肿瘤体积分别为5997.46±1372.90mm3 (NS-3-CIK组),6206.70±1700.61mm3 (NS-7-CIK组)及6387.09±1019.48mm3 (TP组),NS对照组肿瘤体积为7087.57±1103.37mm3。
2.在BALB/c野生鼠CT-26结肠癌模型中,单独CIK免疫治疗或DDP化疗均可明显抑制CT-26结肠癌的生长(P<0.05),而DDP预处理化疗联合CIK细胞免疫治疗与单独治疗组相比,则可诱导更为显著的抗肿瘤作用(P<0.05)。实验结束时DDP-CIK组肿瘤体积为2115.62±436.61mm3,CIK组肿瘤体积为2937.44±773.78mm3,DDP组肿瘤体积为2885.26±318.88mm3,NS对照组肿瘤体积为3867.55±207.56mm3。在BALB/c裸鼠CT-26结肠癌模型中,DDP预处理化疗联合CIK细胞免疫治疗、单独CIK治疗及单独DDP化疗均不能抑制CT-26结肠癌的生长(P>0.05)。实验结束时DDP-CIK组肿瘤体积为3198.15±863.57mm3,CIK组肿瘤体积为3445.42±786.73mm3,DDP组肿瘤体积为3298.26±788.13mm3,NS对照组肿瘤体积为3778.65±819.22mm3。
3.在C57BL/6小鼠B16黑色素瘤模型中,DDP预处理化疗联合CIK细胞免疫治疗可显著抑制B16黑色素瘤的生长(P<0.05),单独的CIK免疫治疗或单独的DDP化疗均不能抑制B16黑色素瘤的生长。实验结束时DDP-CIK组肿瘤体积为2644.41±910.8mm3,CIK组肿瘤体积为5634.08±486.89mm3,DDP组肿瘤体积为5215.31±1118.87mm3,NS对照组肿瘤体积为5587.62±1390.01mm3。
4. Lewis(?)市癌模型中的TP预处理化疗可促进过继性输注的CIK细胞至肿瘤局灶及脾脏组织的归巢。
5. Lewis(?)市癌模型中的TP预处理化疗及CT-26结肠癌模型中的DDP预处理化疗均可促进CD3+T淋巴细胞至肿瘤局灶的浸润,而对肿瘤组织的微血管密度无明显作用。
6.预处理化疗可以诱导肿瘤引流淋巴结(Tumor-draining lymph nodes, TDLNs)及肿瘤组织中内源性T淋巴细胞比例的一过性升高；增加骨髓、外周血及脾脏组织中DCs的比例；降低外周血、骨髓、脾脏组织及TDLNs中MDSCs的比例；下调肿瘤局灶及脾脏组织中Treg细胞的比例。
7.化疗药物预处理可增加人肺腺癌细胞对CIK细胞体外杀伤作用的敏感性。
8.化疗药物预处理可上调人肺腺癌细胞ULBP、Fas、ICAM-1及DNAM分子1mRNA水平的表达,下调Clr-b分子mRNA水平的表达。
[结论与意义]
1.预处理化疗可在多种动物肿瘤模型中增强CIK细胞免疫治疗的疗效,且此种增效作用与宿主的内源性T淋巴细胞相关。
2.预处理化疗可通过调节机体的免疫内环境以促进CIK细胞至肿瘤及脾脏组织的归巢,增强CIK细胞免疫治疗的疗效。
3.预处理化疗可能通过调节肿瘤细胞免疫原性相关分子的表达以调变肿瘤细胞的免疫原性,进而增加肿瘤细胞对CIK细胞体外杀伤作用的敏感性。
4.综上所述,本研究首次证实预处理化疗可增强CIK细胞免疫治疗在多种动物肿瘤模型中的抗肿瘤作用,并发现这种增强作用与预处理化疗可调节机体免疫微环境及增强肿瘤细胞的免疫原性有关。
5.上述结果为预处理化疗联合CIK细胞免疫治疗的临床应用提供了实验基础与理论依据,也为晚期恶性肿瘤的临床治疗提供了一种安全有效的联合治疗模式。
Background and Objective
It is now clear that chemotherapy, in addition to its direct cytotoxic effects on tumor cells, could exert a profound influence on antitumor immune response. A number of studies have demonstrated that some chemotherapeutic agents could enhance the antitumor activity of subsequent adoptive cell transfer when used as a preconditioning regimen. The purpose of this study was to investigate the enhancement of the antitumor effect of cytokine-induced killer (CIK) cells induced by preconditioning chemotherapy and to elucidate the underlying mechanisms by which chemotherapeutic agents break down the immunosuppressive barriers to release the full potential of the CIK cell therapy.
Materials and Methods
1. C57BL/6 mice were inoculated with Lewis cells to establish the murine lung carcinoma model and then randomly divided into six groups. (a) Group Control:treated with normal saline (NS); (b) Group NS-3-CIK:treated with NS followed 3 days by CIK cells; (c) Group NS-7-CIK:treated with NS followed 7 days by CIK cells; (d) Group TP:treated with TP regimen:paclitaxel (PTX) plus cisplatin (DDP); (e) Group TP-3-CIK:preconditioned with TP regimen followed 3 days by CIK cells; (f) Group TP-7-CIK:preconditioned with TP regimen followed 7 days by CIK cells. Tumor size was monitored as indicator of therapeutic response.
2. BALB/c wild type and BALB/c nu/nu mice were challenged with CT-26 cells to establish the colon adenocarcinoma model and then randomly divided into four groups. (a) Group NS: administered with NS; (b) Group CIK:administered with CIK cells; (c) Group DDP: administered with DDP; (d) Group DDP-CIK:administered with DDP followed 3 days by CIK cells. Tumor size and weight were used as indicators of therapeutic response.
3. C57BL/6 mice were injected with B16 cells to establish the murine melanoma model and then randomly divided into four groups. (a) Group NS:administered with NS; (b) Group CIK: administered with CIK cells; (c) Group DDP:administered with DDP; (d) Group DDP-CIK: administered with DDP followed 3 days by CIK cells. Tumor size was used as indicators of therapeutic response.
4. The in vivo trafficking and homing ability of GFP+ CIK cells were observed by fluorescent microscopy.
5. Immunohistochemistry was performed to observe the intratumoral infiltration of CD3+ T lymphocytes and FoxP3+ regulatory T (Treg) cells and tumor microvessel density.
6. The dynamic changes of endogenous T lymphocytes, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs) and Treg cells in various tissues after preconditioning chemotherapy were analyzed through flow cytometry.
7. The in vitro high, moderate and low toxic concentrations of chemotherapeutic agents were determined by MTT assay and WST-1 assay was used to evaluate the in vitro cytotoxity of CIK cells against drug-treated or untreated tumor cells.
8. RT-PCR was employed to detect the expression of immunogenicity-related molecules of tumor cells in mRNA level after treatment with chemotherapeutic agents.
Results
1. In Lewis lung carcinoma model, CIK cells following TP preconditioning chemotherapy could significantly inhibit the growth of Lewis lung carcinoma (P<0.05), whereas CIK therapy alone or DDP chemotherapy alone failed to induced evident inhibition of tumor growth (P >0.05). At the end of the experiment, the tumor volumes were 3377.82±1603.43mm3 in Group TP-3-CIK,3183.38±806.08mm3 in Group TP-7-CIK,5997.46±1372.90mm3 in Group NS-3-CIK,6206.70±1700.61mm3 in Group NS-7-CIK,6387.09±1019.48mm3 in Group TP and 7087.57±1103.37mm3 in Group NS, respectively.
2. In CT-26 colon adenocarcinoma model, CIK cell therapy alone or DDP alone could markedly inhibit the growth of CT-26 colon adenocarcinoma in BALB/c wild type mice (P<0.05), however the combination of DDP preconditioning chemotherapy and CIK cells could induce more significant tumor growth retardation compared with single therapy (P<0.05). At the end of the experiment in BALB/c wild type mice, the tumor volumes were 2115.62±436.61mm3 in Group DDP-CIK,2937.44±773.78mm3 in Group CIK, 2885.26±318.88mm3 in Group DDP and 3867.55±207.56mm3 in Group NS, respectively. In BALB/c nu/nu mice, the combination therapy and both of the single therapies failed to induce significant tumor growth inhibition (P>0.05). At the end of the experiment in BALB/c nu/nu mice, the tumor volumes were 3198.15±863.57mm3 in Group DDP-CIK, 3445.42±786.73mm3 in Group CIK,3298.26±788.13mm3 in Group DDP and 3778.65±819.22mm3 in Group NS, respectively.
3. In B16 melanoma model, the combination of DDP preconditioning chemotherapy and CIK cells could significantly inhibit the growth of B16 melanoma (P<0.05), whereas CIK therapy alone or DDP chemotherapy alone failed to induced evident inhibition of tumor growth (P >0.05). At the end of the experiment, the tumor volumes were 2644.41±910.8mm3 in Group DDP-CIK,5634.08±486.89mm3 in Group CIK,5215.31±1118.87mm3 in Group DDP and 5587.62±1390.01mm3 in Group NS, respectively.
4. The TP regimen could augment the homing ability of infused CIK cells into tumor and spleen tissues in Lewis lung carcinoma model.
5. The TP regimen in Lewis lung carcinoma model could increase the level of T lymphocytes in local tumor tissues, and DDP preconditioning chemotherapy in CT-26 colon adenocarcinoma model could increase the percentages of endogenous T lymphocytes in tumor tissue and tumor-draining lymph nodes (TDLNs). Neither of the precondition exerted influence on tumor microvessel density.
6. The DDP pretreatment could up-regulate the percentages of DCs in bone marrows, peripheral bloods and spleen tissues, diminish the levels of MDSCs in bone marrows, peripheral bloods, spleen tissues and TDLNs, and decrease the percentages of Treg cells in tumor and spleen tissues.
7. The human lung adenocarcinoma cells displayed an increased sensitivity to the lyses of CIK cells after treatment with chemotherapeutic drugs in vitro.
8. Treatment with chemotherapeutic agents could up-regulate the expression of ULBP, Fas, ICAM-1 and DNAM, and down-regulate the expression of Clr-b in mRNA level in human lung adenocarcinoma cells.
Conclusions
1. Our data indicate that the preconditioning chemotherapy could enhance the antitumor activity of CIK cell therapy in various murine tumor models, and the endogenous T lymphocytes were involved in this enhancement.
2. The underlying mechanisms mediating the chemotherapy-induced enhancement of CIK cells' efficacy may involve the augmentation of homing ability of CIK cells to tumor and spleen tissues, and the modulation of percentages of endogenous immune cells in various tissues.
3. Treatment of chemotherapeutic agents may sensitize tumor cells to the lyses of CIK cells in vitro through up-regulating in the transcriptional expression of immunogenic molecules of target cells.
4. To our knowledge, this is the first study to evaluate the efficacy-enhancing effect of preconditioning chemotherapy on the subsequent adoptive CIK transfer. And this efficacy-enhancing effect may be associated with the modulation of the host immune microenvironment and the immunogenicity of tumor cells induced by chemotherapy.
5. This combined chemo-immunotherapy strategy could be easily translated into a clinical setting and is therefore an attractive modality of combined chemo-immunotherapy applicable to patients with malignant cancer.
传统化疗药物的免疫调节作用已逐渐受到人们的重视,特定剂量特定模式的给药方式可通过多种机制重建机体免疫内环境,调变肿瘤细胞免疫原性。将其作为预处理方案联合后续的过继性细胞免疫治疗,可有效动员机体的免疫系统发挥抗肿瘤作用。本研究旨在观察预处理化疗在小鼠动物肿瘤模型(Lewis(?)市癌、CT-26结肠癌、B16黑色素瘤)中对细胞因子诱导的杀伤细胞(cytokine-induced killer cells, CIK cells)的抗肿瘤活性的增强作用,并从机体免疫内环境的调节以及肿瘤细胞免疫原性的调变两方面探讨介导预处理化疗增效作用的机制。
[材料与方法]
1.建立C57BL/6小鼠Lewis肺癌模型,选用紫杉醇(Paclitaxel, PTX)联合顺铂(Cisplatin, DDP)作为预处理方案(TP方案),荷瘤小鼠随机分为六组：对照组(给予生理盐水,Normal Saline, NS)、NS-3-CIK组(NS后3天给予CIK细胞)、NS-7-CIK组(NS后7天给予CIK细胞)、TP组(给予TP方案)、TP-3-CIK组(TP方案预处理后3天联合CIK细胞)及TP-7-CIK组(TP方案预处理后7天联合CIK细胞)。隔日测量肿瘤长短径监测肿瘤体积,观察各组治疗方案对Lewis肿瘤的抑制作用。
2.分别建立BALB/c野生鼠或BALB/c nu/nu裸鼠CT-26结肠癌模型,随机分为四组：NS组(给予NS)、CIK组(给予CIK细胞)、DDP组(给予DDP)、DDP-CIK组(DDP预处理3天后联合CIK细胞)。隔日测量肿瘤长短径监测肿瘤体积,观察各组治疗方案对CT-26结肠癌的抑制作用,并比较联合方案在两种动物模型中的抗肿瘤作用。
3.建立C57BL/6小鼠B16黑色素瘤模型,随机分为四组：NS组(给予NS)、CIK组(给予CIK细胞)、DDP组(给予DDP)、DDP-CIK组(DDP预处理3天后联合CIK细胞)。隔日测量肿瘤长短径监测肿瘤体积,观察各组治疗方案对B16黑色素瘤的抑制作用。
4.利用绿色荧光蛋白(Green Fluorescence Protein, GFP)转基因小鼠制备GFP+CIK细胞,荧光显微镜追踪其体内迁移分布,观察预处理化疗对CIK细胞体内归巢功能的影响。
5.分离Lewis(?)市癌模型及CT-26结肠癌模型中的肿瘤组织,分别行CD3、FoxP3(Forkhead boxP3)、CD31分子免疫组化染色以评估肿瘤组织局灶T淋巴细胞、Treg细胞的浸润情况以及肿瘤微血管密度的变化。
6.流式细胞术观察预处理化疗后荷瘤鼠各组织中内源性T淋巴细胞、树突状细胞(Dendritic cells, DCs)、髓系来源抑制细胞(Myeloid-derived suppressor cells, MDSCs)、调节性T细胞(Regulatory T cells, Treg cells)的动态变化。
7.MTT法筛选化疗药物5-氟尿嘧啶(5-Fluorouracil,5-FU)、DDP、PTX、多西紫杉醇(Docetaxel,DTX)的体外高、中、低毒性浓度,将这些浓度的化疗药物处理人肺腺癌细胞(A549、SPC-A1、SPC-A1/DTX), WST-1法比较肿瘤细胞在化疗药物预处理前后对CIK细胞体外杀伤作用的敏感性。
8.RT-PCR检测肿瘤细胞经化疗药物处理后各时间点免疫原性分子mRNA水平表达的改变：NKG2D配体(Natural killer group 2, member D ligands, NKG2DL)、Fas受体分子、细胞间黏附分子-1 (Intercellular adhesion molecule-1, ICAM-1)、高迁移率族蛋白1 (High-mobility group box-1, HMGB-1)、钙网织蛋白(Calreticulin, CRT)、DNAM分子(DNAX accessory molecule-1)、Clr-b分子(C-type lectin-related molecule b)。
[结果]
1.在C57BL/6小鼠Lewis肺癌模型中,TP预处理化疗后不同时间点给予CIK细胞免疫治疗均能明显抑制(?)Lewis肺癌的生长(P<0.05),且两时间点间无统计学差异；而单独CIK免疫治疗或TP化疗均不能抑制Lewis肿瘤的生长(P>0.05)。实验结束时两联合治疗组肿瘤体积分别为3377.82±1603.43mm3 (TP-3-CIK组),3183.38±806.08mm3 (TP-7-CIK组);单独CIK治疗组及TP化疗组肿瘤体积分别为5997.46±1372.90mm3 (NS-3-CIK组),6206.70±1700.61mm3 (NS-7-CIK组)及6387.09±1019.48mm3 (TP组),NS对照组肿瘤体积为7087.57±1103.37mm3。
2.在BALB/c野生鼠CT-26结肠癌模型中,单独CIK免疫治疗或DDP化疗均可明显抑制CT-26结肠癌的生长(P<0.05),而DDP预处理化疗联合CIK细胞免疫治疗与单独治疗组相比,则可诱导更为显著的抗肿瘤作用(P<0.05)。实验结束时DDP-CIK组肿瘤体积为2115.62±436.61mm3,CIK组肿瘤体积为2937.44±773.78mm3,DDP组肿瘤体积为2885.26±318.88mm3,NS对照组肿瘤体积为3867.55±207.56mm3。在BALB/c裸鼠CT-26结肠癌模型中,DDP预处理化疗联合CIK细胞免疫治疗、单独CIK治疗及单独DDP化疗均不能抑制CT-26结肠癌的生长(P>0.05)。实验结束时DDP-CIK组肿瘤体积为3198.15±863.57mm3,CIK组肿瘤体积为3445.42±786.73mm3,DDP组肿瘤体积为3298.26±788.13mm3,NS对照组肿瘤体积为3778.65±819.22mm3。
3.在C57BL/6小鼠B16黑色素瘤模型中,DDP预处理化疗联合CIK细胞免疫治疗可显著抑制B16黑色素瘤的生长(P<0.05),单独的CIK免疫治疗或单独的DDP化疗均不能抑制B16黑色素瘤的生长。实验结束时DDP-CIK组肿瘤体积为2644.41±910.8mm3,CIK组肿瘤体积为5634.08±486.89mm3,DDP组肿瘤体积为5215.31±1118.87mm3,NS对照组肿瘤体积为5587.62±1390.01mm3。
4. Lewis(?)市癌模型中的TP预处理化疗可促进过继性输注的CIK细胞至肿瘤局灶及脾脏组织的归巢。
5. Lewis(?)市癌模型中的TP预处理化疗及CT-26结肠癌模型中的DDP预处理化疗均可促进CD3+T淋巴细胞至肿瘤局灶的浸润,而对肿瘤组织的微血管密度无明显作用。
6.预处理化疗可以诱导肿瘤引流淋巴结(Tumor-draining lymph nodes, TDLNs)及肿瘤组织中内源性T淋巴细胞比例的一过性升高；增加骨髓、外周血及脾脏组织中DCs的比例；降低外周血、骨髓、脾脏组织及TDLNs中MDSCs的比例；下调肿瘤局灶及脾脏组织中Treg细胞的比例。
7.化疗药物预处理可增加人肺腺癌细胞对CIK细胞体外杀伤作用的敏感性。
8.化疗药物预处理可上调人肺腺癌细胞ULBP、Fas、ICAM-1及DNAM分子1mRNA水平的表达,下调Clr-b分子mRNA水平的表达。
[结论与意义]
1.预处理化疗可在多种动物肿瘤模型中增强CIK细胞免疫治疗的疗效,且此种增效作用与宿主的内源性T淋巴细胞相关。
2.预处理化疗可通过调节机体的免疫内环境以促进CIK细胞至肿瘤及脾脏组织的归巢,增强CIK细胞免疫治疗的疗效。
3.预处理化疗可能通过调节肿瘤细胞免疫原性相关分子的表达以调变肿瘤细胞的免疫原性,进而增加肿瘤细胞对CIK细胞体外杀伤作用的敏感性。
4.综上所述,本研究首次证实预处理化疗可增强CIK细胞免疫治疗在多种动物肿瘤模型中的抗肿瘤作用,并发现这种增强作用与预处理化疗可调节机体免疫微环境及增强肿瘤细胞的免疫原性有关。
5.上述结果为预处理化疗联合CIK细胞免疫治疗的临床应用提供了实验基础与理论依据,也为晚期恶性肿瘤的临床治疗提供了一种安全有效的联合治疗模式。
Background and Objective
It is now clear that chemotherapy, in addition to its direct cytotoxic effects on tumor cells, could exert a profound influence on antitumor immune response. A number of studies have demonstrated that some chemotherapeutic agents could enhance the antitumor activity of subsequent adoptive cell transfer when used as a preconditioning regimen. The purpose of this study was to investigate the enhancement of the antitumor effect of cytokine-induced killer (CIK) cells induced by preconditioning chemotherapy and to elucidate the underlying mechanisms by which chemotherapeutic agents break down the immunosuppressive barriers to release the full potential of the CIK cell therapy.
Materials and Methods
1. C57BL/6 mice were inoculated with Lewis cells to establish the murine lung carcinoma model and then randomly divided into six groups. (a) Group Control:treated with normal saline (NS); (b) Group NS-3-CIK:treated with NS followed 3 days by CIK cells; (c) Group NS-7-CIK:treated with NS followed 7 days by CIK cells; (d) Group TP:treated with TP regimen:paclitaxel (PTX) plus cisplatin (DDP); (e) Group TP-3-CIK:preconditioned with TP regimen followed 3 days by CIK cells; (f) Group TP-7-CIK:preconditioned with TP regimen followed 7 days by CIK cells. Tumor size was monitored as indicator of therapeutic response.
2. BALB/c wild type and BALB/c nu/nu mice were challenged with CT-26 cells to establish the colon adenocarcinoma model and then randomly divided into four groups. (a) Group NS: administered with NS; (b) Group CIK:administered with CIK cells; (c) Group DDP: administered with DDP; (d) Group DDP-CIK:administered with DDP followed 3 days by CIK cells. Tumor size and weight were used as indicators of therapeutic response.
3. C57BL/6 mice were injected with B16 cells to establish the murine melanoma model and then randomly divided into four groups. (a) Group NS:administered with NS; (b) Group CIK: administered with CIK cells; (c) Group DDP:administered with DDP; (d) Group DDP-CIK: administered with DDP followed 3 days by CIK cells. Tumor size was used as indicators of therapeutic response.
4. The in vivo trafficking and homing ability of GFP+ CIK cells were observed by fluorescent microscopy.
5. Immunohistochemistry was performed to observe the intratumoral infiltration of CD3+ T lymphocytes and FoxP3+ regulatory T (Treg) cells and tumor microvessel density.
6. The dynamic changes of endogenous T lymphocytes, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs) and Treg cells in various tissues after preconditioning chemotherapy were analyzed through flow cytometry.
7. The in vitro high, moderate and low toxic concentrations of chemotherapeutic agents were determined by MTT assay and WST-1 assay was used to evaluate the in vitro cytotoxity of CIK cells against drug-treated or untreated tumor cells.
8. RT-PCR was employed to detect the expression of immunogenicity-related molecules of tumor cells in mRNA level after treatment with chemotherapeutic agents.
Results
1. In Lewis lung carcinoma model, CIK cells following TP preconditioning chemotherapy could significantly inhibit the growth of Lewis lung carcinoma (P<0.05), whereas CIK therapy alone or DDP chemotherapy alone failed to induced evident inhibition of tumor growth (P >0.05). At the end of the experiment, the tumor volumes were 3377.82±1603.43mm3 in Group TP-3-CIK,3183.38±806.08mm3 in Group TP-7-CIK,5997.46±1372.90mm3 in Group NS-3-CIK,6206.70±1700.61mm3 in Group NS-7-CIK,6387.09±1019.48mm3 in Group TP and 7087.57±1103.37mm3 in Group NS, respectively.
2. In CT-26 colon adenocarcinoma model, CIK cell therapy alone or DDP alone could markedly inhibit the growth of CT-26 colon adenocarcinoma in BALB/c wild type mice (P<0.05), however the combination of DDP preconditioning chemotherapy and CIK cells could induce more significant tumor growth retardation compared with single therapy (P<0.05). At the end of the experiment in BALB/c wild type mice, the tumor volumes were 2115.62±436.61mm3 in Group DDP-CIK,2937.44±773.78mm3 in Group CIK, 2885.26±318.88mm3 in Group DDP and 3867.55±207.56mm3 in Group NS, respectively. In BALB/c nu/nu mice, the combination therapy and both of the single therapies failed to induce significant tumor growth inhibition (P>0.05). At the end of the experiment in BALB/c nu/nu mice, the tumor volumes were 3198.15±863.57mm3 in Group DDP-CIK, 3445.42±786.73mm3 in Group CIK,3298.26±788.13mm3 in Group DDP and 3778.65±819.22mm3 in Group NS, respectively.
3. In B16 melanoma model, the combination of DDP preconditioning chemotherapy and CIK cells could significantly inhibit the growth of B16 melanoma (P<0.05), whereas CIK therapy alone or DDP chemotherapy alone failed to induced evident inhibition of tumor growth (P >0.05). At the end of the experiment, the tumor volumes were 2644.41±910.8mm3 in Group DDP-CIK,5634.08±486.89mm3 in Group CIK,5215.31±1118.87mm3 in Group DDP and 5587.62±1390.01mm3 in Group NS, respectively.
4. The TP regimen could augment the homing ability of infused CIK cells into tumor and spleen tissues in Lewis lung carcinoma model.
5. The TP regimen in Lewis lung carcinoma model could increase the level of T lymphocytes in local tumor tissues, and DDP preconditioning chemotherapy in CT-26 colon adenocarcinoma model could increase the percentages of endogenous T lymphocytes in tumor tissue and tumor-draining lymph nodes (TDLNs). Neither of the precondition exerted influence on tumor microvessel density.
6. The DDP pretreatment could up-regulate the percentages of DCs in bone marrows, peripheral bloods and spleen tissues, diminish the levels of MDSCs in bone marrows, peripheral bloods, spleen tissues and TDLNs, and decrease the percentages of Treg cells in tumor and spleen tissues.
7. The human lung adenocarcinoma cells displayed an increased sensitivity to the lyses of CIK cells after treatment with chemotherapeutic drugs in vitro.
8. Treatment with chemotherapeutic agents could up-regulate the expression of ULBP, Fas, ICAM-1 and DNAM, and down-regulate the expression of Clr-b in mRNA level in human lung adenocarcinoma cells.
Conclusions
1. Our data indicate that the preconditioning chemotherapy could enhance the antitumor activity of CIK cell therapy in various murine tumor models, and the endogenous T lymphocytes were involved in this enhancement.
2. The underlying mechanisms mediating the chemotherapy-induced enhancement of CIK cells' efficacy may involve the augmentation of homing ability of CIK cells to tumor and spleen tissues, and the modulation of percentages of endogenous immune cells in various tissues.
3. Treatment of chemotherapeutic agents may sensitize tumor cells to the lyses of CIK cells in vitro through up-regulating in the transcriptional expression of immunogenic molecules of target cells.
4. To our knowledge, this is the first study to evaluate the efficacy-enhancing effect of preconditioning chemotherapy on the subsequent adoptive CIK transfer. And this efficacy-enhancing effect may be associated with the modulation of the host immune microenvironment and the immunogenicity of tumor cells induced by chemotherapy.
5. This combined chemo-immunotherapy strategy could be easily translated into a clinical setting and is therefore an attractive modality of combined chemo-immunotherapy applicable to patients with malignant cancer.
引文
1 Nishimura R, Baker J, Beilhack A, Zeiser R, Olson JA, Sega EI, Karimi M, Negrin RS. In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood 2008; 112:2563-2574
2 Introna M, Borleri G, Conti E, Franceschetti M, Barbui AM, Broady R, Dander E, Gaipa G, D'Amico G, Biagi E, Parma M, Pogliani EM, et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation:a phase I study. Haematologica 2007;927:952-959
3 Jiang J, Xu N, Wu C, Deng H, Lu M, Li M, Xu B, Wu J, Wang R, Xu J, Nilsson-Ehle P. Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res 2006;26:2237-2242
4 Wu C, Jiang J, Shi L, Xu N. Prospective study of chemotherapy in combination with cytokine-induced killer cells in patients suffering from advanced non-small cell lung cancer. Anticancer Res 2008;28:3997-4002
5 Weng DS, Zhou J, Zhou QM, Zhao M, Wang QJ, Huang LX, Li YQ, Chen SP, Wu PH, Xia JC. Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J Immunother 2008;31:63-71
6 Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008;8:59-73
7 Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol.2003; 170(10):4905-13.
8 Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med.2005;202(12):1691-701.
9 Lake RA, van der Most RG. A better way for a cancer cell to die. N Engl J Med. 2006;354(23):2503-4.
10 Gasser S, Raulet DH. The DNA damage response arouses the immune system. Cancer Res. 2006;66(8):3959-62.
11 Yang S, Haluska FG. Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes cells to antigen-specific CTL lysis through perforin/granzyme- and Fas-mediated pathways. J Immunol.2004;172(7):4599-608.
12 Mattarollo SR, Kenna T, Nieda M, et al. Chemotherapy pretreatment sensitizes solid tumor-derived cell lines to V alpha 24+ NKT cell-mediated cytotoxicity. Int J Cancer. 2006; 119(7):1630-7.
13 Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters:how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26(2):111-7.
14 Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and adoptive immunotherapy--how far can we go? Nat Clin Pract Oncol.2006;3(12):668-81.
15 Lake RA, Robinson BM. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer.2005;5(5):397-405
16 Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer.2004;4(6):423-36.
17 Lutsiak ME, Semnani RT, De Pascalis R, et al. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105(7):2862-8.
18 Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol.2004;34(2):336-44.
19 Beyer M, Kochanek M, Darabi K, et al. Reduced frequencies and suppressive function of CD4+CD25+ regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood.2005;106(6):2018-25.
20 Correale P, Cusi MG, Tsang KY, et al. Chemoimmunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J Clin Oncol.2005;23(35):8950-8.
21 Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005;11:6713-21
22 Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F.5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70:3052-61
23 Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007; 13:644-53
24 Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007; 13:5455-62
25 Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model:causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007;13:341-9
26 Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346-57
27 Powell DJ Jr, Dudley ME, Hogan KA, Wunderlich JR, Rosenberg SA. Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion. J Immunol 2006; 177:6527-39
28 Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314:126-9
29 Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity.2004;21(2):137-48.
30 Marincola FM, Jaffee EM, Hicklin DJ, et al. Escape of human solid tumors from T-cell recognition:molecular mechanisms and functional significance. Adv Immunol. 2000;74:181-273.
31 Pardoll DM. Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol.2002;2(4):227-38.
32 Mottet C, Golshayan D. CD4+CD25+Foxp3+ regulatory T cells:from basic research to potential therapeutic use. Swiss Med Wkly.2007;137(45-46):625-34.
33 Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol.2009;9(3):162-74.
1. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001;97:2923-31.
2. Ohtani H. Focus on TILs:prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 2007;7:4.
3. Wang LX, Shu S, Plautz GE. Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells. Cancer Res 2005;65:9547-54.
4. Merlo A, Casalini P, Carcangiu ML, et al. FOXP3 expression and overall survival in breast cancer. J Clin Oncol.2009;27(11):1746-52.
5. Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007; 13:644-53.
6. Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007; 13:5455-62.
7. Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model:causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007;13:341-9.
8. Yu B, Kusmartsev S, Cheng F, Paolini M, Nefedova Y, Sotomayor E, Gabrilovich D. Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer. Clin Cancer Res 2003;9:285-94.
9. Wang J, Kobayashi M, Han M, Choi S, Takano M, Hashino S, Tanaka J, Kondoh T, Kawamura K, Hosokawa M. MyD88 is involved in the signalling pathway for Taxol-induced apoptosis and TNF-alpha expression in human myelomonocytic cells. Br J Haematol 2002; 118:638-45.
10. Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 2005;436:1186-90.
11. Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel MT. Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. J Natl Cancer Inst 1997;89:783-9.
12. Schmidt-Wolf GD, Negrin RS, Schmidt-Wolf IG. Activated T cells and cytokine-induced CD3+CD56+ killer cells. Ann Hematol 1997;74:51-6.
13. Lake RA, Robinson BM. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer 2005;5:397-405.
14. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ, Arnold B, Ganss R. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 2008;453:410-4.
15. Dirkx AE, oude Egbrink MG, Castermans K, van der Schaft DW, Thijssen VL, Dings RP, Kwee L, Mayo KH, Wagstaff J, Bouma-ter Steege JC, Griffioen AW. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J 2006;20:621-30.
16. Webb T. Vascular normalization:study examines how antiangiogenesis therapies work. J Natl Cancer Inst 2005;97:336-7.
17. Fukumura D, Jain RK. Tumor microvasculature and microenvironment:targets for anti-angiogenesis and normalization. Microvasc Res 2007;74:72-84.
18. Sakaguchi S, Powrie F. Emerging challenges in regulatory T cell function and biology. Science 2007;317:627-9.
19. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307.
20. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009;27:186-92.
21. Li H, Yu JP, Cao S, Wei F, Zhang P, An XM, Huang ZT, Ren XB. CD4 +CD25+regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol 2007;27:317-26.
22. Schmidt J, Eisold S, Buchler MW, Marten A. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma. Cancer Immunol Immunother 2004;53:1018-26.
23. Tomura M, Honda T, Tanizaki H, Otsuka A, Egawa G, Tokura Y, Waldmann H, Hori S, Cyster JG, Watanabe T, Miyachi Y, Kanagawa O, et al. Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice. JClin Invest. 2010;120:883-93.
1. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001;97:2923-2931
2. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F.5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70:3052-3061
3. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, Perfettini JL, Schlemmer F, Tasdemir E, Uhl M, Genin P, Civas A, Ryffel B, Kanellopoulos J, Tschopp J, Andre F, Lidereau R, McLaughlin NM, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 2009; 15:1170-1178
4. Golovina TN, Vonderheide RH. Regulatory T cells:overcoming suppression of T-cell immunity. Cancer J 2010; 16:342-347
5. Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, Knolle PA, Thomas RK, von Bergwelt-Baildon M, Debey S, Hallek M, Schultze JL. Reduced percentages and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2005; 106:2018-2025
6. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004;4:423-436
7. Bronte V, Mocellin S. Suppressive influences in the immune response to cancer. J Immunother 2009;32:1-11
8. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346-2357
9. Wang LX, Shu S, Plautz GE. Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells. Cancer Res 2005;65:9547-9554
10. Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S, Tagliabue E, Balsari A. FOXP3 expression and overall survival in breast cancer. JClin Oncol 2009;27:1746-1752
11. Sakaguchi S, Powrie F. Emerging challenges in regulatory T cell function and biology. Science 2007;317:627-9.
12. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307.
13. Colombo MP, Piconese S. Regulatory-T-cell inhibition versus depletion:the right choice in cancer immunotherapy. Nat Rev Cancer 2007;7:880-887
14. Li H, Yu JP, Cao S, Wei F, Zhang P, An XM, Huang ZT, Ren XB. CD4 +CD25+regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol 2007;27:317-26.
15. Schmidt J, Eisold S, Buchler MW, Marten A. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma. Cancer Immunol Immunother 2004;53:1018-26.
16. Dirkx AE, oude Egbrink MG, Castermans K, van der Schaft DW, Thijssen VL, Dings RP, Kwee L, Mayo KH, Wagstaff J, Bouma-ter Steege JC, Griffioen AW. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J2006;20:621-30.
17. Webb T. Vascular normalization:study examines how antiangiogenesis therapies work. JNatl Cancer Inst 2005;97:336-7.
18. Fukumura D, Jain RK. Tumor microvasculature and microenvironment:targets for anti-angiogenesis and normalization. Microvasc Res 2007;74:72-84.
19. Tan GH, Tian L, Wei YQ, Zhao X, Li J, Wu Y, Wen YJ, Yi T, Ding ZY, Kan B, Mao YQ, Deng HX, Li HL, Zou CH, Fu CH. Combination of low-dose cisplatin and recombinant xenogeneic endoglin as a vaccine induces synergistic antitumor activities. Int J Cancer 2004; 112:701-706.
1. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001;97:2923-2931
2. Huang X, Huang G, Song H, Chen L. Preconditioning chemotherapy with paclitaxel and cisplatin enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model. Int J Cancer.2010 Sep 28. [Epub ahead of print]
3. Huang X, Chen Y, Song H, Huang G, Chen L. Cisplatin pretreatment enhances antitumor activity of cytokine-induced killer cells in a T cell dependent manner in a murine colon adenocarcinoma model. World J Gastroentero. Accepted.
4. Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters:how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26(2):111-7.
5. Laurent J, Speiser DE, Appay V, et al. Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients. J Immunother. 2010;33(7):723-34.
6. Ohtani H. Focus on TILs:prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 2007;7:4.
7. Wang LX, Shu S, Plautz GE. Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells. Cancer Res 2005;65:9547-54.
8. Watanabe S, Deguchi K, Zheng R, et al. Tumor-induced CD11b+Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. J Immunol. 2008;181(5):3291-300.
9. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol.2005;23(10):2346-57.
10. Marincola FM, Ferrone S.Immunotherapy of melanoma:the good news, the bad ones and what to do next. Semin Cancer Biol.2003;13(6):387-9.
11. Parmiani G, Castelli C, Rivoltini L, et al. Immunotherapy of melanoma. Semin Cancer Biol. 2003;13(6):391-400.
12. Jorritsma A, Bins AD, Schumacher TN, et al. Skewing the T-cell repertoire by combined DNA vaccination, host conditioning, and adoptive transfer. Cancer Res.2008;68(7):2455-62.
13. Salem ML, Diaz-Montero CM, Al-Khami AA, et al. Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol.2009;182(4):2030-40.
14. Salem ML, Al-Khami AA, El-Naggar SA, et al. Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. Immunol.2010; 184(4):1737-47.
15. Salem ML, El-Naggar SA, Cole DJ. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol.2010;261(2):134-43.
16. Ostrand-Rosenberg S. Myeloid-derived suppressor cells:more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010;59:1593-600
17. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol.2009;9(3):162-74.
18. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells:linking inflammation and cancer. J Immunol.2009;182(8):4499-506.
19. Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, Ochiai A. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer 2009; 125:1276-84
20. Ben-Baruch A. Inflammation-associated immune suppression in cancer:the roles played by cytokines, chemokines and additional mediators. Semin Cancer Biol 2006; 16:38-52
21. Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, Mantovani A. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol 2000; 164:762-7
22. Bak SP, Alonso A, Turk MJ, Berwin B. Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression. Mol Immunol 2008;46:258-68
23. Wrzesinski C, Restifo NP. Less is more:lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin Immunol.2005; 17(2):195-201.
24. Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and adoptive immunotherapy--how far can we go? Nat Clin Pract Oncol.2006;3(12):668-81.
25. Watanabe S, Deguchi K, Zheng R, et al. Tumor-induced CD11b+Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. J Immunol. 2008;181(5):3291-300.
26. Serafini, P., I. Borrello, and V. Bronte.2006. Myeloid suppressor cells in cancer:recruitment, phenotype, properties, and mechanisms of immune suppression. Semin.Cancer Biol.16: 53-65.
27. Ko HJ, Lee JM, Kim YJ, et al. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells:an alternative cell-based antitumor vaccine. J Immunol.2009; 182(4):1818-28.
28. Salem ML, El-Naggar SA, Cole DJ. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol.2010;261(2):134-43.
29. Radojcic V, Bezak KB, Skarica M, et al. Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother.2010;59(1):137-48.
30. Salem ML, Cole DJ. Dendritic cell recovery post-lymphodepletion:a potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer Immunol Immunother. 2010;59(3):341-53.
31. Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest.2007; 117(5):1155-66.
32. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005; 11:6713-21.
33. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F.5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70:3052-61.
34. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity.2004;21(2):137-48.
1. H Sun, L Chen. Mechanism of Drug Resistance Identified in Human Lung Adenocarcinoma Cell Line SPC-A1 Selected for Resistance to Docetaxel. Chin J Cancer Res. 2009;21(3):207-16.
2. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood.2001;97:2923-31.
3. Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007;13:644-53
4. Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007; 13:5455-62
5. Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model:causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007; 13:341-9
6. Huang X, Huang G, Song H, Chen L. Preconditioning chemotherapy with paclitaxel and cisplatin enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model. Int J Cancer.2010 Sep 28. [Epub ahead of print]
7. Huang X, Chen Y, Song H, Huang G, Chen L. Cisplatin pretreatment enhances antitumor activity of cytokine-induced killer cells in a T cell dependent manner in a murine colon adenocarcinoma model. World J Gastroentero. Accepted.
8. Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol.2003;170(10):4905-13.
9. Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med.2005;202(12):1691-701.
10. Lake RA, Robinson BM. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer.2005;5(5):397-405.
11. Mehta BA, Schmidt-Wolf IG, Weissman IL, et al. Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells. Blood. 1995;86(9):3493-9.
12. Verneris MR, Kornacker M, Mailander V, et al. Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis. Cancer Immunol Immunother.2000;49(6):335-45.
13. Verneris MR, Karami M, Baker J, et al. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood.2004;103(8):3065-72.
14. Gasser S, Raulet DH. The DNA damage response arouses the immune system. Cancer Res. 2006;66(8):3959-62.
15. Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel MT. Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. J Natl Cancer Inst 1997;89:783-789.
16. Yang S, Haluska FG. Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes cells to antigen-specific CTL lysis through perforin/granzyme- and Fas-mediated pathways. J Immunol 2004; 172:4599-608.
17. Soriani A, Zingoni A, Cerboni C, et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood.2009;113(15):3503-11.
18. Iizuka K, Naidenko OV, Plougastel BF, et al. Genetically linked C-type lectin-related ligands for the NKRP1 family of natural killer cell receptors. Nat Immunol.2003;4(8):801-7.
19. Raulet DH. Missing self recognition and self tolerance of natural killer (NK) cells. Semin Immunol.2006; 18(3):145-50.
20. Green DR, Ferguson T, Zitvogel L, et al. Immunogenic and tolerogenic cell death. Nat Rev Immunol.2009;9(5):353-63.
21. Apetoh L, Ghiringhelli F, Tesniere A, et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev. 2007;220:47-59.
22. Tesniere A, Panaretakis T, Kepp O, et al. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ.2008;15(1):3-12.
23. Panaretakis T, Kepp O, Brockmeier U, et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J.2009;28(5):578-90.
1. Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer:a clinical path to effective cancer immunotherapy. Nat Rev Cancer.2008;8(4):299-308.
2. Schmidt-Wolf IG, Lefterova P, Johnston V, et al. Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells. Cell Immunol.1996; 169(1):85-90.
3. Schmidt-Wolf IG, Lefterova P, Mehta BA, et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol.1993;21(13):1673-9.
4. Schmidt-Wolf IG, Negrin RS, Kiem HP, et al. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med. 1991;174(1):139-49.
5. Lu PH, Negrin RS. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol.1994; 153(4):1687-96.
6. Mehta BA, Schmidt-Wolf IG, Weissman IL, et al. Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells. Blood. 1995;86(9):3493-9.
7. Verneris MR, Kornacker M, Mailander V, et al. Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis. Cancer Immunol Immunother.2000;49(6):335-45.
8. Verneris MR, Karami M, Baker J, et al. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood.2004;103(8):3065-72.
9. Kornacker M, Moldenhauer G, Herbst M, et al. Cytokine-induced killer cells against autologous CLL:direct cytotoxic effects and induction of immune accessory molecules by interferon-gamma. Int J Cancer.2006; 119(6):1377-82.
10. Linn YC, Lau SK, Liu BH, et al. Characterization of the recognition and functional heterogeneity exhibited by cytokine-induced killer cell subsets against acute myeloid leukaemia target cell. Immunology.2009;126(3):423-35.
11. Franceschetti M, Pievani A, Borleri G, et al. Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol. 2009;37(5):616-28.
12. Yu J, Ren X, Cao S, et al. Th1 polarization and apoptosis-inducing activity of CD4+ T-cells in cytokine-induced killers might favor the antitumor cytotoxicity of cytokine-induced killers in vivo. Cancer Biother Radiopharm.2006;21(3):276-84.
13. Yu J, Zhang W, Jiang H, et al. CD4+T cells in CIKs(CD4+ CIKs) reversed resistance to fas-mediated apoptosis through CD40/CD40L ligation rather than IFN-gamma stimulation. Cancer Biother Radiopharm.2008;23(3):342-54.
14. Leemhuis T, Wells S, Scheffold C, et al. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant.2005;11(3):181-7.
15. Introna M, Borleri G, Conti E, et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation:a phase I study. Haematologica.2007;92(7):952-9.
16. Sangiolo D, Martinuzzi E, Todorovic M, et al. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer(CIK) cells:implications for their infusion across major HLA barriers. Int Immunol.2008;20(7):841-8.
17. Nishimura R, Baker J, Beilhack A, et al. In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood. 2008;112(6):2563-74.
18. Jiang J, Xu N, Wu C, et al. Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res.2006;26(3B):2237-42.
19. Wu C, Jiang J, Shi L, Xu N. Prospective study of chemotherapy in combination with cytokine-induced killer cells in patients suffering from advanced non-small cell lung cancer. Anticancer Res.2008;28(6B):3997-4002.
20. Hui D, Qiang L, Jian W, et al. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis.2009;41(1):36-41.
21.袁香庆,崔传亮,斯璐,等.化疗联合CIK回输治疗专一性急肾细胞癌Ⅱ期临床研究.肿瘤学杂志.2008；14(5)：352-5.
22.斯璐,迟志宏,袁香庆,等.晚期黑素瘤过继免疫治疗的癌Ⅱ期临床研究.肿瘤.2008；28(7)：591-5.
23. Pang J. Enhanced Antitumor Effects by the Coculture of Allotumor RNA-Pulsed Dendritic Cells with Autologous Cytokine-Induced Killer Cells on Hormone-Refractory Prostate Cancer. Cancer Invest.2007;18:1-8.
24. Zoll B, Lefterova P, Csipai M, et al. Generation of cytokine-induced killer cells using exogenous interleukin-2,-7 or -12. Cancer Immunol Immunother.1998;47(4):221-6.
25. Marin V, Kakuda H, Dander E, et al. Enhancement of the anti-leukemic activity of cytokine induced killer cells with an anti-CD19 chimeric receptor delivering a 4-1BB-zeta activating signal. Exp Hematol.2007;35(9):1388-97.
26. Marin V, Dander E, Biagi E, et al. Characterization of in vitro migratory properties of anti-CD 19 chimeric receptor-redirected CIK cells for their potential use in B-ALL immunotherapy. Exp Hematol.2006;34(9):1219-29.
27. Tita-Nwa F, Moldenhauer G, Herbst M, et al. Cytokine-induced killer cells targeted by the novel bispecific antibody CD19xCD5(HD37xT5.16) efficiently lyse B-lymphoma cells. Cancer Immunol Immunother.2007;56(12):1911-20.
28. Mottet C, Golshayan D. CD4+CD25+Foxp3+ regulatory T cells:from basic research to potential therapeutic use. Swiss Med Wkly.2007;137(45-46):625-34.
29. Gattinoni L, Powell DJ Jr, Rosenberg SA, et al. Adoptive immunotherapy for cancer:building on success. Nat Rev Immunol.2006;6(5):383-93.
30. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity.2004;21(2):137-48.
31. Marincola FM, Jaffee EM, Hicklin DJ, et al. Escape of human solid tumors from T-cell recognition:molecular mechanisms and functional significance. Adv Immunol. 2000;74:181-273.
32. Pardoll DM. Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol.2002;2(4):227-38.
33.陈龙邦.抗肿瘤化疗与抗肿瘤免疫.医学研究生学报.2008；21(2)：113-4.
34. Lake RA, Robinson BM. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer.2005;5(5):397-405.
35. Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol.2003; 170(10):4905-13.
36. Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med.2005;202(12):1691-701.
37. Green DR, Ferguson T, Zitvogel L, et al. Immunogenic and tolerogenic cell death. Nat Rev Immunol.2009;9(5):353-63.
38. Gasser S, Raulet DH. The DNA damage response arouses the immune system. Cancer Res. 2006;66(8):3959-62.
39. van der Most RG, Currie A, Robinson BW, et al. Cranking the immunologic engine with chemotherapy:using context to drive tumor antigen cross-presentation towards useful antitumor immunity. Cancer Res.2006;66(2):601-4.
40. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells:Which signals induce tolerance or immunity? Trends Immunol.2002;23(9):445-9.
41. Rad AN, Pollara G, Sohaib SM, et al. The differential influence of allogeneic tumor cell death via DNA damage on dendritic cell maturation and antigen presentation. Cancer Res. 2003;63(16):5143-50.
42. Nowak AK, Robinson BW, Lake RA. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res.2003;63(15):4490-6.
43. Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters:how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26(2):111-7.
44. Machiels JP, Reilly RT, Emens LA, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 2001;61(9):3689-97.
45. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer.2004;4(6):423-36.
46. Lutsiak ME, Semnani RT, De Pascalis R, et al. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105(7):2862-8.
47. Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol.2004;34(2):336-44.
48. Beyer M, Kochanek M, Darabi K, et al. Reduced frequencies and suppressive function of CD4+CD25+ regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood.2005;106(6):2018-25.
49. Correale P, Cusi MG, Tsang KY, et al. Chemoimmunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J Clin Oncol.2005;23(35):8950-8.
50. Yang S, Haluska FG. Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes cells to antigen-specific CTL lysis through perforin/granzyme- and Fas-mediated pathways. J Immunol.2004;172(7):4599-608.
51. Mattarollo SR, Kenna T, Nieda M, et al. Chemotherapy pretreatment sensitizes solid tumor-derived cell lines to V alpha 24+ NKT cell-mediated cytotoxicity. Int J Cancer. 2006; 119(7):1630-7.
52. Wherry EJ, Barber DL, Kaech SM, et al. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc Natl Acad Sci USA.2004; 101 (45):16004-9.
53. Polak L, Turk JL. Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity. Nature.1974;249(458):654-6.
54. Laurent J, Speiser DE, Appay V, et al. Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients. J Immunother. 2010;33(7):723-34.
55. Salem ML, Cole DJ. Dendritic cell recovery post-lymphodepletion:a potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer Immunol Immunother. 2010;59(3):341-53.
56. Ibe S, Qin Z, Schiiler T, et al. Tumor rejection by disturbing tumor stroma cell interactions. J Exp Med.2001;194(11):1549-59.
57. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol.2005;23(10):2346-57.
58. Ghiringhelli F, Menard C, Puig PE,et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother.2007;56(5):641-8.
59. Correale P, Aquino A, Giuliani A, et al. Treatment of colon and breast carcinoma cells with 5-fluorouracil enhances expression of carcinoembryonic antigen and susceptibility to HLA-A(*)02.01 restricted, CEA-peptide-specific cytotoxic T cells in vitro. Int J Cancer. 2003;104(4):437-45.
60. Vincent J, Mignot G, Chalmin F, et al.5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70(8):3052-61.
61. Weihrauch MR, Ansen S, Jurkiewicz E, et al. Phase Ⅰ/Ⅱ Combined Chemoimmunotherapy with Carcinoembryonic Antigen-Derived HLA-A2-Restricted CAP-1 Peptide and Irinotecan,5-Fluorouracil, and Leucovorin in Patients with Primary Metastatic Colorectal Cancer. Clin Cancer Res.2005 Aug 15;11(16):5993-6001.
62. Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral immune response:implications for combination chemo-immunotherapy. Cancer Res. 2002;62(8):2353-8.
63. Suzuki E, Kapoor V, Jassar AS, et al. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res.2005; 11 (18):6713-21.
64. Levitt ML, Kassem B, Gooding WE, et al. Phase Ⅰ study of gemcitabine given weekly as a short infusion for non-small cell lung cancer:results and possible immune system-related mechanisms. Lung Cancer.2004;43(3):335-44.
65. Plate JM, Plate AE, Shott S, Bograd S, Harris JE. Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother. 2005;54(9):915-25.
66. Eralp Y, Wang X, Wang JP, et al. Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER 2/neu in a murine mammary carcinoma model. Breast Cancer Res.2004;6(4):R275-83.
67. Hashino S, Tanaka J, Kondoh T, et al. MyD88 is involved in the signalling pathway for Taxol-induced apoptosis and TNF-alpha expression in human myelomonocytic cells. Br J Haematol.2002; 118(2):638-45.
68. Yu B, Kusmartsev S, Cheng F, et al. Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer. Clin Cancer Res.2003;9(1):285-94.
69. Demaria S, Volm MD, Shapiro RL, et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res. 2001;7(10):3025-30.
70. Garnett CT, Schlom J, Hodge JW. Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity:effects of docetaxel on immune enhancement. Clin Cancer Res.2008;14(11):3536-44.
71. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008;8(1):59-73.
72. Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007; 13(2 Pt 1):644-53.
73. Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007; 13(18 Pt 1):5455-62.
74. Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model:causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007; 13:341-9.
75. Powell DJ Jr, Dudley ME, Hogan KA, Wunderlich JR, Rosenberg SA. Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion. J Immunol 2006; 177:6527-39.
76. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314:126-9.
77. Dudley ME, Wunderlich JR, Yang JC, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother.2002;25:243-51.
78. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science.2002;298:850-4.
79. Zhou J, Dudley ME, Rosenberg SA, et al. Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy. J Immunother.2005;28(1):53-62.
80. Dudley ME, Rosenberg SA. Adoptive Cell Transfer Therapy. Semin Oncol.2007;34(6): 524-531.
81. June CH. Principles of adoptive T cell cancer therapy. J Clin Invest.2007; 117(5):1204-12.
82. Gattinoni L, Powell DJ Jr, Rosenberg SA, et al. Adoptive immunotherapy for cancer:building on success. Nat Rev Immunol.2006;6(5):383-93.
83. Wrzesinski C, Restifo NP. Less is more:lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin Immunol.2005; 17(2):195-201.
84. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma:evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol.2008;26(32):5233-9.
85. Heemskerk B, Liu K, Dudley ME, et al. Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum Gene Ther. 2008;19(5):496-510.
86. Besser MJ, Shapira-Frommer R, Treves AJ, et al. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients. J Immunother.2009;32(4):415-23.
87. Wallen H, Thompson JA, Reilly JZ, et al. Fludarabine modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells in patients with metastatic melanoma. PLoS One.2009;4(3):e4749.
88. Appay V, Voelter V, Rufer N, et al. Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma. J Immunother.2007;30:240-250.
89. Khammari A, Labarriere N, Vignard V, et al. Treatment of metastatic melanoma with autologous Melan-A/MART-1-specific cytotoxic T lymphocyte clones. J Invest Dermatol. 2009;129(12):2835-42.
90. Hong JJ, Rosenberg SA, Dudley ME, et al. Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin Cancer Res.2010;16(19):4892-8.
91. Austin EB, Stern PL, Hawkins RE. Adoptive transfer of T(reg) depleted autologous T cells in advanced renal cell carcinoma. Cancer Immunol Immunother.2008;57(5):623-34.
92. Li H, Yu JP, Cao S, et al. CD4 +CD25+regulatory T cells decreased the antitumor activity of cytokine-induced killer(CIK) cells of lung cancer patients. J Clin Immunol. 2007;27(3):317-26.
93. Schmidt J, Eisold S, Buchler MW, et al. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma. Cancer Immunol Immunother.2004;53(11):1018-26.
94. Marten A, Ziske C, Sch?ttker B, et al. Interactions between dendritic cells and cytokine-induced killer cells lead to an activation of both populations. J Immunother. 2001;24(6):502-10.
95. Ostrand-Rosenberg S. Myeloid-derived suppressor cells:more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010;59:1593-600
96. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol.2009;9(3):162-74.
97. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells:linking inflammation and cancer. J Immunol.2009;182(8):4499-506.
98. Salem ML, Diaz-Montero CM, Al-Khami AA, et al. Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol.2009;182(4):2030-40.
99. Salem ML, Al-Khami AA, El-Naggar SA, et al. Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. Immunol.2010; 184(4):1737-47.
100. Salem ML, El-Naggar SA, Cole DJ. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol.2010;261(2):134-43.
2 Introna M, Borleri G, Conti E, Franceschetti M, Barbui AM, Broady R, Dander E, Gaipa G, D'Amico G, Biagi E, Parma M, Pogliani EM, et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation:a phase I study. Haematologica 2007;927:952-959
3 Jiang J, Xu N, Wu C, Deng H, Lu M, Li M, Xu B, Wu J, Wang R, Xu J, Nilsson-Ehle P. Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res 2006;26:2237-2242
4 Wu C, Jiang J, Shi L, Xu N. Prospective study of chemotherapy in combination with cytokine-induced killer cells in patients suffering from advanced non-small cell lung cancer. Anticancer Res 2008;28:3997-4002
5 Weng DS, Zhou J, Zhou QM, Zhao M, Wang QJ, Huang LX, Li YQ, Chen SP, Wu PH, Xia JC. Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J Immunother 2008;31:63-71
6 Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008;8:59-73
7 Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol.2003; 170(10):4905-13.
8 Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med.2005;202(12):1691-701.
9 Lake RA, van der Most RG. A better way for a cancer cell to die. N Engl J Med. 2006;354(23):2503-4.
10 Gasser S, Raulet DH. The DNA damage response arouses the immune system. Cancer Res. 2006;66(8):3959-62.
11 Yang S, Haluska FG. Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes cells to antigen-specific CTL lysis through perforin/granzyme- and Fas-mediated pathways. J Immunol.2004;172(7):4599-608.
12 Mattarollo SR, Kenna T, Nieda M, et al. Chemotherapy pretreatment sensitizes solid tumor-derived cell lines to V alpha 24+ NKT cell-mediated cytotoxicity. Int J Cancer. 2006; 119(7):1630-7.
13 Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters:how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26(2):111-7.
14 Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and adoptive immunotherapy--how far can we go? Nat Clin Pract Oncol.2006;3(12):668-81.
15 Lake RA, Robinson BM. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer.2005;5(5):397-405
16 Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer.2004;4(6):423-36.
17 Lutsiak ME, Semnani RT, De Pascalis R, et al. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105(7):2862-8.
18 Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol.2004;34(2):336-44.
19 Beyer M, Kochanek M, Darabi K, et al. Reduced frequencies and suppressive function of CD4+CD25+ regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood.2005;106(6):2018-25.
20 Correale P, Cusi MG, Tsang KY, et al. Chemoimmunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J Clin Oncol.2005;23(35):8950-8.
21 Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005;11:6713-21
22 Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F.5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70:3052-61
23 Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007; 13:644-53
24 Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007; 13:5455-62
25 Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model:causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007;13:341-9
26 Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346-57
27 Powell DJ Jr, Dudley ME, Hogan KA, Wunderlich JR, Rosenberg SA. Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion. J Immunol 2006; 177:6527-39
28 Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314:126-9
29 Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity.2004;21(2):137-48.
30 Marincola FM, Jaffee EM, Hicklin DJ, et al. Escape of human solid tumors from T-cell recognition:molecular mechanisms and functional significance. Adv Immunol. 2000;74:181-273.
31 Pardoll DM. Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol.2002;2(4):227-38.
32 Mottet C, Golshayan D. CD4+CD25+Foxp3+ regulatory T cells:from basic research to potential therapeutic use. Swiss Med Wkly.2007;137(45-46):625-34.
33 Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol.2009;9(3):162-74.
1. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001;97:2923-31.
2. Ohtani H. Focus on TILs:prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 2007;7:4.
3. Wang LX, Shu S, Plautz GE. Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells. Cancer Res 2005;65:9547-54.
4. Merlo A, Casalini P, Carcangiu ML, et al. FOXP3 expression and overall survival in breast cancer. J Clin Oncol.2009;27(11):1746-52.
5. Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007; 13:644-53.
6. Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007; 13:5455-62.
7. Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model:causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007;13:341-9.
8. Yu B, Kusmartsev S, Cheng F, Paolini M, Nefedova Y, Sotomayor E, Gabrilovich D. Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer. Clin Cancer Res 2003;9:285-94.
9. Wang J, Kobayashi M, Han M, Choi S, Takano M, Hashino S, Tanaka J, Kondoh T, Kawamura K, Hosokawa M. MyD88 is involved in the signalling pathway for Taxol-induced apoptosis and TNF-alpha expression in human myelomonocytic cells. Br J Haematol 2002; 118:638-45.
10. Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 2005;436:1186-90.
11. Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel MT. Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. J Natl Cancer Inst 1997;89:783-9.
12. Schmidt-Wolf GD, Negrin RS, Schmidt-Wolf IG. Activated T cells and cytokine-induced CD3+CD56+ killer cells. Ann Hematol 1997;74:51-6.
13. Lake RA, Robinson BM. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer 2005;5:397-405.
14. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ, Arnold B, Ganss R. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 2008;453:410-4.
15. Dirkx AE, oude Egbrink MG, Castermans K, van der Schaft DW, Thijssen VL, Dings RP, Kwee L, Mayo KH, Wagstaff J, Bouma-ter Steege JC, Griffioen AW. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J 2006;20:621-30.
16. Webb T. Vascular normalization:study examines how antiangiogenesis therapies work. J Natl Cancer Inst 2005;97:336-7.
17. Fukumura D, Jain RK. Tumor microvasculature and microenvironment:targets for anti-angiogenesis and normalization. Microvasc Res 2007;74:72-84.
18. Sakaguchi S, Powrie F. Emerging challenges in regulatory T cell function and biology. Science 2007;317:627-9.
19. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307.
20. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009;27:186-92.
21. Li H, Yu JP, Cao S, Wei F, Zhang P, An XM, Huang ZT, Ren XB. CD4 +CD25+regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol 2007;27:317-26.
22. Schmidt J, Eisold S, Buchler MW, Marten A. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma. Cancer Immunol Immunother 2004;53:1018-26.
23. Tomura M, Honda T, Tanizaki H, Otsuka A, Egawa G, Tokura Y, Waldmann H, Hori S, Cyster JG, Watanabe T, Miyachi Y, Kanagawa O, et al. Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice. JClin Invest. 2010;120:883-93.
1. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001;97:2923-2931
2. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F.5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70:3052-3061
3. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, Perfettini JL, Schlemmer F, Tasdemir E, Uhl M, Genin P, Civas A, Ryffel B, Kanellopoulos J, Tschopp J, Andre F, Lidereau R, McLaughlin NM, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 2009; 15:1170-1178
4. Golovina TN, Vonderheide RH. Regulatory T cells:overcoming suppression of T-cell immunity. Cancer J 2010; 16:342-347
5. Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, Knolle PA, Thomas RK, von Bergwelt-Baildon M, Debey S, Hallek M, Schultze JL. Reduced percentages and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2005; 106:2018-2025
6. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004;4:423-436
7. Bronte V, Mocellin S. Suppressive influences in the immune response to cancer. J Immunother 2009;32:1-11
8. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346-2357
9. Wang LX, Shu S, Plautz GE. Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells. Cancer Res 2005;65:9547-9554
10. Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S, Tagliabue E, Balsari A. FOXP3 expression and overall survival in breast cancer. JClin Oncol 2009;27:1746-1752
11. Sakaguchi S, Powrie F. Emerging challenges in regulatory T cell function and biology. Science 2007;317:627-9.
12. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307.
13. Colombo MP, Piconese S. Regulatory-T-cell inhibition versus depletion:the right choice in cancer immunotherapy. Nat Rev Cancer 2007;7:880-887
14. Li H, Yu JP, Cao S, Wei F, Zhang P, An XM, Huang ZT, Ren XB. CD4 +CD25+regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol 2007;27:317-26.
15. Schmidt J, Eisold S, Buchler MW, Marten A. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma. Cancer Immunol Immunother 2004;53:1018-26.
16. Dirkx AE, oude Egbrink MG, Castermans K, van der Schaft DW, Thijssen VL, Dings RP, Kwee L, Mayo KH, Wagstaff J, Bouma-ter Steege JC, Griffioen AW. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J2006;20:621-30.
17. Webb T. Vascular normalization:study examines how antiangiogenesis therapies work. JNatl Cancer Inst 2005;97:336-7.
18. Fukumura D, Jain RK. Tumor microvasculature and microenvironment:targets for anti-angiogenesis and normalization. Microvasc Res 2007;74:72-84.
19. Tan GH, Tian L, Wei YQ, Zhao X, Li J, Wu Y, Wen YJ, Yi T, Ding ZY, Kan B, Mao YQ, Deng HX, Li HL, Zou CH, Fu CH. Combination of low-dose cisplatin and recombinant xenogeneic endoglin as a vaccine induces synergistic antitumor activities. Int J Cancer 2004; 112:701-706.
1. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001;97:2923-2931
2. Huang X, Huang G, Song H, Chen L. Preconditioning chemotherapy with paclitaxel and cisplatin enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model. Int J Cancer.2010 Sep 28. [Epub ahead of print]
3. Huang X, Chen Y, Song H, Huang G, Chen L. Cisplatin pretreatment enhances antitumor activity of cytokine-induced killer cells in a T cell dependent manner in a murine colon adenocarcinoma model. World J Gastroentero. Accepted.
4. Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters:how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26(2):111-7.
5. Laurent J, Speiser DE, Appay V, et al. Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients. J Immunother. 2010;33(7):723-34.
6. Ohtani H. Focus on TILs:prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 2007;7:4.
7. Wang LX, Shu S, Plautz GE. Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells. Cancer Res 2005;65:9547-54.
8. Watanabe S, Deguchi K, Zheng R, et al. Tumor-induced CD11b+Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. J Immunol. 2008;181(5):3291-300.
9. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol.2005;23(10):2346-57.
10. Marincola FM, Ferrone S.Immunotherapy of melanoma:the good news, the bad ones and what to do next. Semin Cancer Biol.2003;13(6):387-9.
11. Parmiani G, Castelli C, Rivoltini L, et al. Immunotherapy of melanoma. Semin Cancer Biol. 2003;13(6):391-400.
12. Jorritsma A, Bins AD, Schumacher TN, et al. Skewing the T-cell repertoire by combined DNA vaccination, host conditioning, and adoptive transfer. Cancer Res.2008;68(7):2455-62.
13. Salem ML, Diaz-Montero CM, Al-Khami AA, et al. Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol.2009;182(4):2030-40.
14. Salem ML, Al-Khami AA, El-Naggar SA, et al. Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. Immunol.2010; 184(4):1737-47.
15. Salem ML, El-Naggar SA, Cole DJ. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol.2010;261(2):134-43.
16. Ostrand-Rosenberg S. Myeloid-derived suppressor cells:more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010;59:1593-600
17. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol.2009;9(3):162-74.
18. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells:linking inflammation and cancer. J Immunol.2009;182(8):4499-506.
19. Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, Ochiai A. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer 2009; 125:1276-84
20. Ben-Baruch A. Inflammation-associated immune suppression in cancer:the roles played by cytokines, chemokines and additional mediators. Semin Cancer Biol 2006; 16:38-52
21. Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, Mantovani A. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol 2000; 164:762-7
22. Bak SP, Alonso A, Turk MJ, Berwin B. Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression. Mol Immunol 2008;46:258-68
23. Wrzesinski C, Restifo NP. Less is more:lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin Immunol.2005; 17(2):195-201.
24. Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and adoptive immunotherapy--how far can we go? Nat Clin Pract Oncol.2006;3(12):668-81.
25. Watanabe S, Deguchi K, Zheng R, et al. Tumor-induced CD11b+Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. J Immunol. 2008;181(5):3291-300.
26. Serafini, P., I. Borrello, and V. Bronte.2006. Myeloid suppressor cells in cancer:recruitment, phenotype, properties, and mechanisms of immune suppression. Semin.Cancer Biol.16: 53-65.
27. Ko HJ, Lee JM, Kim YJ, et al. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells:an alternative cell-based antitumor vaccine. J Immunol.2009; 182(4):1818-28.
28. Salem ML, El-Naggar SA, Cole DJ. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol.2010;261(2):134-43.
29. Radojcic V, Bezak KB, Skarica M, et al. Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother.2010;59(1):137-48.
30. Salem ML, Cole DJ. Dendritic cell recovery post-lymphodepletion:a potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer Immunol Immunother. 2010;59(3):341-53.
31. Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest.2007; 117(5):1155-66.
32. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005; 11:6713-21.
33. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F.5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70:3052-61.
34. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity.2004;21(2):137-48.
1. H Sun, L Chen. Mechanism of Drug Resistance Identified in Human Lung Adenocarcinoma Cell Line SPC-A1 Selected for Resistance to Docetaxel. Chin J Cancer Res. 2009;21(3):207-16.
2. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood.2001;97:2923-31.
3. Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007;13:644-53
4. Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007; 13:5455-62
5. Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model:causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007; 13:341-9
6. Huang X, Huang G, Song H, Chen L. Preconditioning chemotherapy with paclitaxel and cisplatin enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model. Int J Cancer.2010 Sep 28. [Epub ahead of print]
7. Huang X, Chen Y, Song H, Huang G, Chen L. Cisplatin pretreatment enhances antitumor activity of cytokine-induced killer cells in a T cell dependent manner in a murine colon adenocarcinoma model. World J Gastroentero. Accepted.
8. Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol.2003;170(10):4905-13.
9. Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med.2005;202(12):1691-701.
10. Lake RA, Robinson BM. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer.2005;5(5):397-405.
11. Mehta BA, Schmidt-Wolf IG, Weissman IL, et al. Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells. Blood. 1995;86(9):3493-9.
12. Verneris MR, Kornacker M, Mailander V, et al. Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis. Cancer Immunol Immunother.2000;49(6):335-45.
13. Verneris MR, Karami M, Baker J, et al. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood.2004;103(8):3065-72.
14. Gasser S, Raulet DH. The DNA damage response arouses the immune system. Cancer Res. 2006;66(8):3959-62.
15. Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel MT. Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. J Natl Cancer Inst 1997;89:783-789.
16. Yang S, Haluska FG. Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes cells to antigen-specific CTL lysis through perforin/granzyme- and Fas-mediated pathways. J Immunol 2004; 172:4599-608.
17. Soriani A, Zingoni A, Cerboni C, et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood.2009;113(15):3503-11.
18. Iizuka K, Naidenko OV, Plougastel BF, et al. Genetically linked C-type lectin-related ligands for the NKRP1 family of natural killer cell receptors. Nat Immunol.2003;4(8):801-7.
19. Raulet DH. Missing self recognition and self tolerance of natural killer (NK) cells. Semin Immunol.2006; 18(3):145-50.
20. Green DR, Ferguson T, Zitvogel L, et al. Immunogenic and tolerogenic cell death. Nat Rev Immunol.2009;9(5):353-63.
21. Apetoh L, Ghiringhelli F, Tesniere A, et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev. 2007;220:47-59.
22. Tesniere A, Panaretakis T, Kepp O, et al. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ.2008;15(1):3-12.
23. Panaretakis T, Kepp O, Brockmeier U, et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J.2009;28(5):578-90.
1. Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer:a clinical path to effective cancer immunotherapy. Nat Rev Cancer.2008;8(4):299-308.
2. Schmidt-Wolf IG, Lefterova P, Johnston V, et al. Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells. Cell Immunol.1996; 169(1):85-90.
3. Schmidt-Wolf IG, Lefterova P, Mehta BA, et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol.1993;21(13):1673-9.
4. Schmidt-Wolf IG, Negrin RS, Kiem HP, et al. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med. 1991;174(1):139-49.
5. Lu PH, Negrin RS. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol.1994; 153(4):1687-96.
6. Mehta BA, Schmidt-Wolf IG, Weissman IL, et al. Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells. Blood. 1995;86(9):3493-9.
7. Verneris MR, Kornacker M, Mailander V, et al. Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis. Cancer Immunol Immunother.2000;49(6):335-45.
8. Verneris MR, Karami M, Baker J, et al. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood.2004;103(8):3065-72.
9. Kornacker M, Moldenhauer G, Herbst M, et al. Cytokine-induced killer cells against autologous CLL:direct cytotoxic effects and induction of immune accessory molecules by interferon-gamma. Int J Cancer.2006; 119(6):1377-82.
10. Linn YC, Lau SK, Liu BH, et al. Characterization of the recognition and functional heterogeneity exhibited by cytokine-induced killer cell subsets against acute myeloid leukaemia target cell. Immunology.2009;126(3):423-35.
11. Franceschetti M, Pievani A, Borleri G, et al. Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol. 2009;37(5):616-28.
12. Yu J, Ren X, Cao S, et al. Th1 polarization and apoptosis-inducing activity of CD4+ T-cells in cytokine-induced killers might favor the antitumor cytotoxicity of cytokine-induced killers in vivo. Cancer Biother Radiopharm.2006;21(3):276-84.
13. Yu J, Zhang W, Jiang H, et al. CD4+T cells in CIKs(CD4+ CIKs) reversed resistance to fas-mediated apoptosis through CD40/CD40L ligation rather than IFN-gamma stimulation. Cancer Biother Radiopharm.2008;23(3):342-54.
14. Leemhuis T, Wells S, Scheffold C, et al. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant.2005;11(3):181-7.
15. Introna M, Borleri G, Conti E, et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation:a phase I study. Haematologica.2007;92(7):952-9.
16. Sangiolo D, Martinuzzi E, Todorovic M, et al. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer(CIK) cells:implications for their infusion across major HLA barriers. Int Immunol.2008;20(7):841-8.
17. Nishimura R, Baker J, Beilhack A, et al. In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood. 2008;112(6):2563-74.
18. Jiang J, Xu N, Wu C, et al. Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res.2006;26(3B):2237-42.
19. Wu C, Jiang J, Shi L, Xu N. Prospective study of chemotherapy in combination with cytokine-induced killer cells in patients suffering from advanced non-small cell lung cancer. Anticancer Res.2008;28(6B):3997-4002.
20. Hui D, Qiang L, Jian W, et al. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis.2009;41(1):36-41.
21.袁香庆,崔传亮,斯璐,等.化疗联合CIK回输治疗专一性急肾细胞癌Ⅱ期临床研究.肿瘤学杂志.2008；14(5)：352-5.
22.斯璐,迟志宏,袁香庆,等.晚期黑素瘤过继免疫治疗的癌Ⅱ期临床研究.肿瘤.2008；28(7)：591-5.
23. Pang J. Enhanced Antitumor Effects by the Coculture of Allotumor RNA-Pulsed Dendritic Cells with Autologous Cytokine-Induced Killer Cells on Hormone-Refractory Prostate Cancer. Cancer Invest.2007;18:1-8.
24. Zoll B, Lefterova P, Csipai M, et al. Generation of cytokine-induced killer cells using exogenous interleukin-2,-7 or -12. Cancer Immunol Immunother.1998;47(4):221-6.
25. Marin V, Kakuda H, Dander E, et al. Enhancement of the anti-leukemic activity of cytokine induced killer cells with an anti-CD19 chimeric receptor delivering a 4-1BB-zeta activating signal. Exp Hematol.2007;35(9):1388-97.
26. Marin V, Dander E, Biagi E, et al. Characterization of in vitro migratory properties of anti-CD 19 chimeric receptor-redirected CIK cells for their potential use in B-ALL immunotherapy. Exp Hematol.2006;34(9):1219-29.
27. Tita-Nwa F, Moldenhauer G, Herbst M, et al. Cytokine-induced killer cells targeted by the novel bispecific antibody CD19xCD5(HD37xT5.16) efficiently lyse B-lymphoma cells. Cancer Immunol Immunother.2007;56(12):1911-20.
28. Mottet C, Golshayan D. CD4+CD25+Foxp3+ regulatory T cells:from basic research to potential therapeutic use. Swiss Med Wkly.2007;137(45-46):625-34.
29. Gattinoni L, Powell DJ Jr, Rosenberg SA, et al. Adoptive immunotherapy for cancer:building on success. Nat Rev Immunol.2006;6(5):383-93.
30. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity.2004;21(2):137-48.
31. Marincola FM, Jaffee EM, Hicklin DJ, et al. Escape of human solid tumors from T-cell recognition:molecular mechanisms and functional significance. Adv Immunol. 2000;74:181-273.
32. Pardoll DM. Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol.2002;2(4):227-38.
33.陈龙邦.抗肿瘤化疗与抗肿瘤免疫.医学研究生学报.2008；21(2)：113-4.
34. Lake RA, Robinson BM. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer.2005;5(5):397-405.
35. Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol.2003; 170(10):4905-13.
36. Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med.2005;202(12):1691-701.
37. Green DR, Ferguson T, Zitvogel L, et al. Immunogenic and tolerogenic cell death. Nat Rev Immunol.2009;9(5):353-63.
38. Gasser S, Raulet DH. The DNA damage response arouses the immune system. Cancer Res. 2006;66(8):3959-62.
39. van der Most RG, Currie A, Robinson BW, et al. Cranking the immunologic engine with chemotherapy:using context to drive tumor antigen cross-presentation towards useful antitumor immunity. Cancer Res.2006;66(2):601-4.
40. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells:Which signals induce tolerance or immunity? Trends Immunol.2002;23(9):445-9.
41. Rad AN, Pollara G, Sohaib SM, et al. The differential influence of allogeneic tumor cell death via DNA damage on dendritic cell maturation and antigen presentation. Cancer Res. 2003;63(16):5143-50.
42. Nowak AK, Robinson BW, Lake RA. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res.2003;63(15):4490-6.
43. Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters:how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26(2):111-7.
44. Machiels JP, Reilly RT, Emens LA, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 2001;61(9):3689-97.
45. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer.2004;4(6):423-36.
46. Lutsiak ME, Semnani RT, De Pascalis R, et al. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105(7):2862-8.
47. Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol.2004;34(2):336-44.
48. Beyer M, Kochanek M, Darabi K, et al. Reduced frequencies and suppressive function of CD4+CD25+ regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood.2005;106(6):2018-25.
49. Correale P, Cusi MG, Tsang KY, et al. Chemoimmunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J Clin Oncol.2005;23(35):8950-8.
50. Yang S, Haluska FG. Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes cells to antigen-specific CTL lysis through perforin/granzyme- and Fas-mediated pathways. J Immunol.2004;172(7):4599-608.
51. Mattarollo SR, Kenna T, Nieda M, et al. Chemotherapy pretreatment sensitizes solid tumor-derived cell lines to V alpha 24+ NKT cell-mediated cytotoxicity. Int J Cancer. 2006; 119(7):1630-7.
52. Wherry EJ, Barber DL, Kaech SM, et al. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc Natl Acad Sci USA.2004; 101 (45):16004-9.
53. Polak L, Turk JL. Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity. Nature.1974;249(458):654-6.
54. Laurent J, Speiser DE, Appay V, et al. Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients. J Immunother. 2010;33(7):723-34.
55. Salem ML, Cole DJ. Dendritic cell recovery post-lymphodepletion:a potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer Immunol Immunother. 2010;59(3):341-53.
56. Ibe S, Qin Z, Schiiler T, et al. Tumor rejection by disturbing tumor stroma cell interactions. J Exp Med.2001;194(11):1549-59.
57. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol.2005;23(10):2346-57.
58. Ghiringhelli F, Menard C, Puig PE,et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother.2007;56(5):641-8.
59. Correale P, Aquino A, Giuliani A, et al. Treatment of colon and breast carcinoma cells with 5-fluorouracil enhances expression of carcinoembryonic antigen and susceptibility to HLA-A(*)02.01 restricted, CEA-peptide-specific cytotoxic T cells in vitro. Int J Cancer. 2003;104(4):437-45.
60. Vincent J, Mignot G, Chalmin F, et al.5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70(8):3052-61.
61. Weihrauch MR, Ansen S, Jurkiewicz E, et al. Phase Ⅰ/Ⅱ Combined Chemoimmunotherapy with Carcinoembryonic Antigen-Derived HLA-A2-Restricted CAP-1 Peptide and Irinotecan,5-Fluorouracil, and Leucovorin in Patients with Primary Metastatic Colorectal Cancer. Clin Cancer Res.2005 Aug 15;11(16):5993-6001.
62. Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral immune response:implications for combination chemo-immunotherapy. Cancer Res. 2002;62(8):2353-8.
63. Suzuki E, Kapoor V, Jassar AS, et al. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res.2005; 11 (18):6713-21.
64. Levitt ML, Kassem B, Gooding WE, et al. Phase Ⅰ study of gemcitabine given weekly as a short infusion for non-small cell lung cancer:results and possible immune system-related mechanisms. Lung Cancer.2004;43(3):335-44.
65. Plate JM, Plate AE, Shott S, Bograd S, Harris JE. Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother. 2005;54(9):915-25.
66. Eralp Y, Wang X, Wang JP, et al. Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER 2/neu in a murine mammary carcinoma model. Breast Cancer Res.2004;6(4):R275-83.
67. Hashino S, Tanaka J, Kondoh T, et al. MyD88 is involved in the signalling pathway for Taxol-induced apoptosis and TNF-alpha expression in human myelomonocytic cells. Br J Haematol.2002; 118(2):638-45.
68. Yu B, Kusmartsev S, Cheng F, et al. Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer. Clin Cancer Res.2003;9(1):285-94.
69. Demaria S, Volm MD, Shapiro RL, et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res. 2001;7(10):3025-30.
70. Garnett CT, Schlom J, Hodge JW. Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity:effects of docetaxel on immune enhancement. Clin Cancer Res.2008;14(11):3536-44.
71. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008;8(1):59-73.
72. Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007; 13(2 Pt 1):644-53.
73. Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007; 13(18 Pt 1):5455-62.
74. Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model:causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007; 13:341-9.
75. Powell DJ Jr, Dudley ME, Hogan KA, Wunderlich JR, Rosenberg SA. Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion. J Immunol 2006; 177:6527-39.
76. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314:126-9.
77. Dudley ME, Wunderlich JR, Yang JC, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother.2002;25:243-51.
78. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science.2002;298:850-4.
79. Zhou J, Dudley ME, Rosenberg SA, et al. Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy. J Immunother.2005;28(1):53-62.
80. Dudley ME, Rosenberg SA. Adoptive Cell Transfer Therapy. Semin Oncol.2007;34(6): 524-531.
81. June CH. Principles of adoptive T cell cancer therapy. J Clin Invest.2007; 117(5):1204-12.
82. Gattinoni L, Powell DJ Jr, Rosenberg SA, et al. Adoptive immunotherapy for cancer:building on success. Nat Rev Immunol.2006;6(5):383-93.
83. Wrzesinski C, Restifo NP. Less is more:lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin Immunol.2005; 17(2):195-201.
84. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma:evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol.2008;26(32):5233-9.
85. Heemskerk B, Liu K, Dudley ME, et al. Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum Gene Ther. 2008;19(5):496-510.
86. Besser MJ, Shapira-Frommer R, Treves AJ, et al. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients. J Immunother.2009;32(4):415-23.
87. Wallen H, Thompson JA, Reilly JZ, et al. Fludarabine modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells in patients with metastatic melanoma. PLoS One.2009;4(3):e4749.
88. Appay V, Voelter V, Rufer N, et al. Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma. J Immunother.2007;30:240-250.
89. Khammari A, Labarriere N, Vignard V, et al. Treatment of metastatic melanoma with autologous Melan-A/MART-1-specific cytotoxic T lymphocyte clones. J Invest Dermatol. 2009;129(12):2835-42.
90. Hong JJ, Rosenberg SA, Dudley ME, et al. Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin Cancer Res.2010;16(19):4892-8.
91. Austin EB, Stern PL, Hawkins RE. Adoptive transfer of T(reg) depleted autologous T cells in advanced renal cell carcinoma. Cancer Immunol Immunother.2008;57(5):623-34.
92. Li H, Yu JP, Cao S, et al. CD4 +CD25+regulatory T cells decreased the antitumor activity of cytokine-induced killer(CIK) cells of lung cancer patients. J Clin Immunol. 2007;27(3):317-26.
93. Schmidt J, Eisold S, Buchler MW, et al. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma. Cancer Immunol Immunother.2004;53(11):1018-26.
94. Marten A, Ziske C, Sch?ttker B, et al. Interactions between dendritic cells and cytokine-induced killer cells lead to an activation of both populations. J Immunother. 2001;24(6):502-10.
95. Ostrand-Rosenberg S. Myeloid-derived suppressor cells:more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010;59:1593-600
96. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol.2009;9(3):162-74.
97. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells:linking inflammation and cancer. J Immunol.2009;182(8):4499-506.
98. Salem ML, Diaz-Montero CM, Al-Khami AA, et al. Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol.2009;182(4):2030-40.
99. Salem ML, Al-Khami AA, El-Naggar SA, et al. Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. Immunol.2010; 184(4):1737-47.
100. Salem ML, El-Naggar SA, Cole DJ. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol.2010;261(2):134-43.