甘露糖-6-磷酸受体在恶性肿瘤免疫治疗联合化疗中的作用
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摘要
研究目的
1.通过构建不同肿瘤动物模型,验证免疫治疗联合化疗的增效作用。通过体外观察化疗药物对不同肿瘤细胞甘露糖-6-磷酸受体(M6PR)的影响以及相应小鼠肿瘤模型体内肿瘤细胞M6PR的表达变化,探讨化疗对肿瘤细胞M6PR的作用。构建表达荧光素酶的野生型(H2Kb+/+)B16F10细胞(B16-Luc)及B16F10H2Kb-/细胞(B16-H2Kb-)。用control shRNA或是M6PR shRNA转染B16-H2Kb细胞,分别建立其肿瘤小鼠模型并给与不同治疗方法,体内验证M6PR在免疫治疗联合化疗中的作用。
2.观察体内、外化疗后不同肿瘤细胞M6PR mRNA及其蛋白表达情况,同时检测肿瘤细胞内M6PR主要配体IGF-Ⅱ水平的变化。体外观察化疗药物对肿瘤细胞自噬现象的影响。通过上调以及阻断细胞自噬,观察化疗对M6PR在肿瘤细胞内的分布情况,探讨IGF-Ⅱ及自噬在免疫治疗联合化疗中的作用。
研究方法
1.应用流式细胞仪检测B16F10恶性黑色素瘤、4T1乳腺癌以及人多发性骨髓瘤U266肿瘤细胞系,经化疗后肿瘤细胞表面MPR的表达状况。分别建立上述肿瘤小鼠模型,应用免疫组化方法动态检测化疗后肿瘤组织中M6PR的表达水平。构建表达荧光素酶的野生型(H2Kb+/+)B16F10细胞(B16-Luc)及B16F10H2Kb-/-细胞(B16-H2Kb-)。用control shRNA或是M6PR shRNA转染B16-H2Kb-细胞,分别建立其肿瘤小鼠模型,分别给与不同治疗方案,采用直接测量肿瘤大小以及活体成像技术动态监测肿瘤进展。
2.采用Real-time PCR和Western blotting方法检测体内、外经TAX、DOX化疗后B16F10、4T1、U266肿瘤细胞M6PR mRNA以及M6PR总蛋白和膜蛋白表达情况。应用免疫组化和Western blotting方法检测上述肿瘤细胞内M6PR主要配体IGF-II水平的变化,探索化疗上调肿瘤细胞表面M6PR的潜在机制。应用激光共聚焦显微镜观察化疗药物对肿瘤细胞自噬现象的影响。通过自噬抑制剂3-MA或atg5siRNA下调自噬以及通过自噬诱导剂Rapamycin上调自噬,应用流式细胞仪和共聚焦显微镜观察化疗对M6PR在肿瘤细胞内的分布情况。
结果
1.免疫治疗联合化疗的抗肿瘤效应
在MC38结肠癌小鼠模型中,与无治疗模型对照组相比,单一p53DC疫苗免疫治疗延缓了肿瘤的进展(P<0.05),单一TAX化疗也延缓了肿瘤的生长,但是治疗一经停止肿瘤迅速进展。与单一治疗相比,免疫治疗联合化疗显著的抑制了肿瘤的生长(P<0.05)。在TUBO乳腺癌小鼠模型中,与无治疗模型对照组相比,单一TAX化疗没有显著的抗肿瘤作用(P>0.05),单一Neu DC疫苗有轻微延缓肿瘤生长的作用(P>0.05)。与单一治疗相比,DC疫苗联合TAX治疗产生了显著的抗肿瘤效果(P<0.05)。在EG-7淋巴瘤小鼠模型中,与无治疗模型对照组相比,单一过继性T细胞免疫治疗或是TAX化疗均导致肿瘤缩小(P<0.05)。与单一治疗相比,联合治疗的抗肿瘤效应显著增强(P<0.05)。
2.化疗对肿瘤细胞表面M6PR的影响
(1)小鼠B16F10恶性黑色素瘤、4T1乳腺癌以及人多发性骨髓瘤8226、929、U266多种肿瘤细胞体外经化疗后细胞表面M6PR均上调性表达(P<0.05)。上述肿瘤细胞经化疗后摄取颗粒酶B也显著增加(P<0.05)。在B16F10恶性黑色素瘤、4T1乳腺癌小鼠模型中,TAX给药48小时后,免疫组化显示肿瘤组织M6PR表达显著性上调(P<0.05)。在给药后72小时,M6PR仍保持较高状态,在给药后5天其恢复到治疗前水平。在U266人多发性骨髓瘤裸鼠模型中,经DOX治疗后M6PR发生同样的变化。
(2)在B16F10荷瘤小鼠,与无治疗对照相比,单一Pme1-1CTLs或是TAX显著的抑制了肿瘤的生长,但是停止治疗后一周肿瘤继续增长。TAX联合T细胞治疗抗肿瘤效应显著增强(P<0.05)。T细胞输入2天之后给与TAX出现上述增强效应；而T细胞输入5天之前给与TAX,未观察到增强效应。
3.M6PR在化疗联合免疫治疗的抗肿瘤效应中的作用
(1)在转染了control shRNA的B16F10荷瘤小鼠中,与单一治疗相比,TAX联合Pme1-1CTL治疗抗肿瘤效应显著增强(P<0.05)。在转染了M6PR shRNA的荷瘤小鼠中,联合治疗未显示出增强作用(P>0.05)。
(2)在B16F10M6PR shRNA Kb荷瘤小鼠中,与未治疗对照相比,单一Trp2180-188CTLs未显示抗肿瘤活性(P>0.05)。与单一TAX化疗相比,联合治疗未显示出增强作用(P>0.05)。在B16F10control shRNA Kb荷瘤小鼠中,联合治疗也未显示出增强作用(P>0.05)。
(3)在B16F10-Luc(左侧肋腹)、control shRNA Kb"(右侧肋腹)双侧肿瘤小鼠模型中,针对B16F10-Luc肿瘤,联合治疗比单一免疫治疗或化疗显示出增强的抗肿瘤效应(P<0.05)；针对control shRNA Kb肿瘤,联合治疗未显示出增强作用(P>0.05)。在B16-Luc与control shRNA Kb-混合肿瘤模型中,与单一治疗相比,联合治疗导致肿瘤总体积显著缩小(P<0.05)。应用活体成像技术监测肿瘤组织中的B16F10-Luc细胞,联合治疗比单一免疫治疗或化疗显示出增强的抗肿瘤效应(P<0.05)。在B16-Luc与M6PR shRNA Kb-混合肿瘤模型中,与单一治疗相比,联合治疗未导致肿瘤总体积缩小(P>0.05)。应用活体成像技术监测肿瘤组织中的B16F10-Luc细胞,联合治疗比单一免疫治疗或化疗显示出增强的抗肿瘤效应(P<0.05)。
4.化疗对肿瘤细胞内M6PR合成、讲解以及再分布的影响(1)Real-time PCR结果显示,在M6PR mRNA表达水平上,化疗药物对B16F10、4T1和EL-4肿瘤细胞没有显著影响(P>0.05)。流式细胞分析数据显示,B16F10或是4T1肿瘤细胞经过TAX处理后,细胞表面上的M6PR被上调表达(P<0.05),细胞内M6PR总蛋白表达水平没有发生变化(P>0.05)。Western blotting结果显示,用TAX处理B16F10细胞或是用DOX处理EL-4、U266细胞后,M6PR总蛋白表达水平没有明显变化(P>0.05), M6PR膜蛋白水平显著增加(P<0.05)。
(2)激光共聚焦显微镜结果显示,在U266肿瘤细胞内化疗前M6PR集中在细胞浆内,而化疗后其主要定位于细胞膜；在多发性骨髓瘤患者骨髓切片中,治疗前只有20%的肿瘤细胞出现M6PR在细胞膜上的聚集现象,化疗后3天该比例增至50%以上(P<0.05)。
5.自噬对肿瘤细胞内M6PR再分布的影响
(1)流式细胞分析结果显示,经TAX预处理的B16F10细胞体外与重组IGF-Ⅱ共同孵育,细胞表面M6PR上调表达的能力缺失,细胞摄取颗粒酶B的能力也明显下降(P<0.05)。Western blotting结果显示,化疗药物体外对4T1、EL4、B16F10三种肿瘤细胞内IGF-Ⅱ表达水平没有显著作用(P>0.05)；4T1和B16F10荷瘤小鼠经TAX体内处理后,肿瘤组织中IGF-Ⅱ水平显著增加(P<0.05)。
(2)激光共聚焦显微镜结果显示,应用TAX、CIS、DOX处理肿瘤细胞后,自噬被迅速诱导。应用3-MA抑制自噬,DOX原先诱导的U266细胞表面M6PR的上调表达能力明显下降(P<0.05)；经过TAX处理后的B16F10细胞也出现此现象。应用atg5siRNA转染B16F10细胞下调自噬,TAX原先诱导的细胞膜M6PR的上调性表达现象显著下降(P<0.05)。应用Rapamycin诱导自噬,肿瘤细胞表面的M6PR明显增加(P<0.05)。用LC3-GFP转染B16F10肿瘤细胞,未经化疗处理的细胞没有观察到M6PR和LC3的共定位；细胞经TAX处理之后,更容易观察到自噬小体和M6PR的共定位现象。
结论
化疗可以增强CTL免疫治疗的效果,而该效应与M6PR介导的细胞内吞相关。化疗后肿瘤细胞表面M6PR的短暂诱导介导了化疗联合免疫治疗的旁观者效应,有利于二者产生协同作用。该作用与化疗诱导的自噬相关,而与肿瘤细胞内的IGF-Ⅱ水平无关。
Objective
1. To confirm the potentiation of the antitumor effects of immunotherapy in combination with chemotherapy by the investigation of different kinds of tumors established in mice. To test the effect of chemotherapy on M6PR in tumor cells by the treatment of B16F10,4T1or U266tumor cells in vitro and their tumors established in mice in vivo with chemotherapy. To test the role of M6PR in the combined therapy in vivo wild-type (H2Kb+/+) B16F10cells expressing luciferase (B16-Luc) and B16F10H2Kb-/-cells (B16-H2Kb-) were used. B16-H2Kb-cells were transfected with control or MPR shRNA and their tumors established in mice were treated with different therapy.
2. To investigate the mechanism of MPR up-regulation by chemotherapy through detecting the mpr mRNA and its protein expression in B16F10,4T1or U266cells in vitro and their tumors established in mice in vivo with chemotherapy. To study the association between MPR up-regulation and the expression of IGF-Ⅱ in tumor cells treated with chemotherapy. To test the in tumor cells induced by chemotherapy in vitro. To test the hypothesis of potentiating antitumor effects of immunotherapy combined with chemotherapy through investigating the re-distribution of M6PR in tumor cells by the up-regulation or down-regulation of autophagy.
Methods
1. The expression of M6PR on the surface of B16F10,4T1or U266tumor cells after chemotherapy was evaluated by flow cytometry. The M6PR protein levels in B16F10,4T1or U266tumors established in mice after chemotherapy were evaluated by Immunohistochemistry. wild-type (H2Kb+/+) B16F10cells expressing luciferase (B16-Luc) and B16F10H2Kb-/-cells (B16-H2Kb-) were used. B16-H2Kb-cells were transfected with control or MPR shRNA and their tumors established in mice were treated with different therapy. Tumor growth was monitored three times a week by caliper measurement and twice a week by in vivo imaging.
2. The mpr mRNA level in B16F10,4T1or U266cells in vitro and in vivo after chemotherapy was evaluated by Real-time PCR. The total M6PR protein and membrane fractions in these tumor cells were detected by Western blotting. The IGF-II protein level in tumor cells treated with chemotherapy was evaluated by Western blotting in order to study the mechanism of MPR up-regulation by chemotherapy. The autophagy in tumor cells induced by chemotherapy was evaluated by confocal microscopy. The re-distribution of M6PR in tumor cells after chemotherapy was detected using confocal microscopy and flow cytometry through the blockade of autophagy with either its inhibitor3MA or down-regulating atg5and through the up-regulation of autophagy with Rapamycin.
Results
1. The antitumor effect of immunotherapy combined with chemotherapy In MC38colon carcinoma models, Vaccination of mice with DCs transduced with adenovirus containing full-length mouse wild-type p53(Ad-p53) resulted in a substantial delay in tumor progression compared with no treatment (P<0.05). Treatment of mice with TAX alone delayed tumor growth, but tumor progression resumed soon after the treatment was discontinued. The combination of TAX and the DC vaccine potently suppressed tumor growth compared with either immunotherapy or chemotherapy alone (P<0.05). In TUBO breast carcinoma models, single TAX had very little antitumor activity and vaccination alone only slightly delayed tumor growth compared with no treatment (P>0.05). The combination of the DC vaccine with TAX treatment resulted in a substantial antitumor effect in this model as well (P<0.05).In EG-7lymphoma models, T cells or TAX alone caused a decrease in tumor growth compared with no treatment (P<0.05). This effect was substantially more pronounced when T cell transfer and TAX administration were combined (P<0.05).
2. The effect of chemotherapy on M6PR on tumor cell surface
(1) Several mouse (B16F10melanoma,4T1mammary carcinoma) and human multiple myeloma (8226, H929, U266) tumor cell lines were used to test the effects of chemotherapy on the expression of MPR. Different chemotherapeutic agents caused substantial and similar up-regulation of MPR expression in vitro in all tested mouse and human tumor cell lines (P<0.05). Chemotherapy also increased granzyme B (GrzB) penetration into cells (P<0.05).In B16F10,4T1tumor models significant (P<0.05) up-regulation of MPR expression was detected48hr after the injection of TAX using immunohistochemistry. It remained elevated for another24hr and then returned to the pre-treatment level within5days after injection. It also happened in U266tumors in nude mice treated with DOX.
(2) In B16F10tumor bearing mice, administration of either Pmel-1CTLs or TAX alone substantially delayed tumor growth, which however, resumed one week after the treatment. When TAX was combined with T-cell therapy, a significant (P<0.05) potentiating effect was observed. However, this effect was seen only if TAX was administered two days after T cells. When TAX was injected5days prior to T-cell administration, no increased antitumor effect was observed.
3. The role of M6PR in the effect of immunotherapy combined with chemotherapy
(1) In B16F10control shRNA tumor bearing mice, Pmel-1CTLs combined with TAX resulted in an increased antitumor effect compared with single therapy (P<0.05). In B16F10M6PR shRNA tumor bearing mice, no increased antitumor effect was observed in combination therapy (P>0.05).
(2) In B16F10M6PR shRNA Kb-tumor bearing mice, single Trp2180-188CTLs did not show any antitumor effect compared with no treatment (P>0.05). No increased antitumor effect was observed in combination therapy compared with single TAX (.P>0.05). In B16F10control shRNA Kb" tumor bearing mice, no increased antitumor effect was observed in combination therapy (P>0.05).
(3) B16-Luc and B16-control shRNA Kb-tumors were established in the opposite flanks (B16-Luc-left flank; B16-control shRNA Kb--right flank) of the same mouse. Significant (P<0.05) potentiation of the antitumor effects of combined TAX and CTLs was observed only in the flank with B16-Luc tumor but not with B16-control shRNA Kb" tumors. In the B16-Luc mixed with control shRNA Kb-tumor bearing mice, combining TAX and CTLs resulted in a significantly (P<0.05) greater antitumor effect than each of them separately. This was seen by monitoring tumor size with calipers and by in vivo imaging. In the B16-Luc mixed with M6PR shRNA Kb-tumor bearing mice, potentiation of the antitumor effect of combination therapy was not detected (P>0.05) while TAX and CTLs combined had potent antitumor activity against B16-Luc cells when these cells were monitored by in vivo imaging (P<0.05).
4. The effect of chemotherapy on MPR synthesis, degradation and re-distribution
(1) The result of Real-time PCR showed that no effect of chemotherapy drugs on mpr mRNA expression was found in B16F10,4T1and EL-4tumor cells (P>0.05). Treatment of B16F10or4T1tumor cells in vitro with TAX resulted in up-regulation of MPR on the cell surface (P>0.05). However, when the total amount of MPR was evaluated using Western blot, no effect of TAX or DOX on MPR was found. Similar results were obtained when cells were analyzed by flow cytometry after fixation and permeabilization prior to staining with anti-MPR antibody (P>0.05).In these tumor cell lines treated with TAX or DOX, chemotherapy induced substantial accumulation of MPR only in a membrane fraction (P<0.05).
(2) We evaluated MPR expression in human MM U266cells treated with DOX using confocal microscopy. Chemotherapy caused redistribution of MPR from a primarily cytoplasmic to a predominantly membrane localization of MPR. We assessed the proportion of MM cells with predominantly membrane localization of MPR using bone marrow slides from MM patietns. Prior to treatment only20%of the MM cells had such a characteristic, whereas after3days of high-dose chemotherapy this proportion increased to more than50%of all MM cells (P<0.05).
5. The effect of autophagy on the re-distribution of M6PR in tumor cells
(1) The flow data showed that incubation of B16F10tumor cells with recombinant IGF-Ⅱ led to the loss of the tumor cell's ability to up-regulate MPR expression on the surface in response to TAX. This was associated with loss of TAX-inducible up-regulation of GrzB uptake by tumor cells (P<0.05). The effect of chemotherapy on4T1, EL4. and B16F10tumor cell lines in vitro were evaluated by Western blotting. In all cases no decrease in IGF-II expression was detected (P>0.05). We also tested the in vivo effect of TAX treatment in4T1and B16F10tumor-bearing mice. Chemotherapy treatment caused a substantial increase in the level of IGF-2(P>0.05).
(2) Treatment of tumor cells with TAX, CIS, or DOX caused rapid induction of autophagy as determined by the appearance of autophagy-specific LC3punctae in treated cells by confocal microscopy. Inhibition of autophagy with3MA abrogated up-regulation of MPR on the surface of U266MM cells treated with DOX or B16F10cells treated with TAX (P<0.05). Transfection of B16F10cells with atg5siRNA completely abrogated the TAX-inducible increase in MPR expression (P<0.05). Rapamycin caused a substantial increase in MPR levels on the tumor cell surface (P<0.05). B16F10tumor cells were transfected with LC3-GFP. After treatment of the cells with TAX, LC3punctae became easily visualized by confocal microscopy. When untreated cells were stained with MPR antibody, no co-localization of MPR and LC3were seen. In contrast, after TAX, co-localization of autophagosomes and MPR was readily detectable.
Conclusion
Cancer immunotherapy in combination with chemotherapy may produce an increased antitumor effect. The antitumor effect of CTL is associated with endocytosis induced by M6PR. Chemotherapy combined with immunotherapy results in bystander killing of tumor cells without the need for antigen recognition and this effect was mediated by MPR. Chemotherapy dose not induce MPR synthesis or inhibit its degradation. Changes in IGF-2levels caused by chemotherapy were not associated with up-regulation of MPR on the tumor cell surface. Chemotherapy-inducible autophagy causes up-regulation of MPR on tumor cell surface.
1.通过构建不同肿瘤动物模型,验证免疫治疗联合化疗的增效作用。通过体外观察化疗药物对不同肿瘤细胞甘露糖-6-磷酸受体(M6PR)的影响以及相应小鼠肿瘤模型体内肿瘤细胞M6PR的表达变化,探讨化疗对肿瘤细胞M6PR的作用。构建表达荧光素酶的野生型(H2Kb+/+)B16F10细胞(B16-Luc)及B16F10H2Kb-/细胞(B16-H2Kb-)。用control shRNA或是M6PR shRNA转染B16-H2Kb细胞,分别建立其肿瘤小鼠模型并给与不同治疗方法,体内验证M6PR在免疫治疗联合化疗中的作用。
2.观察体内、外化疗后不同肿瘤细胞M6PR mRNA及其蛋白表达情况,同时检测肿瘤细胞内M6PR主要配体IGF-Ⅱ水平的变化。体外观察化疗药物对肿瘤细胞自噬现象的影响。通过上调以及阻断细胞自噬,观察化疗对M6PR在肿瘤细胞内的分布情况,探讨IGF-Ⅱ及自噬在免疫治疗联合化疗中的作用。
研究方法
1.应用流式细胞仪检测B16F10恶性黑色素瘤、4T1乳腺癌以及人多发性骨髓瘤U266肿瘤细胞系,经化疗后肿瘤细胞表面MPR的表达状况。分别建立上述肿瘤小鼠模型,应用免疫组化方法动态检测化疗后肿瘤组织中M6PR的表达水平。构建表达荧光素酶的野生型(H2Kb+/+)B16F10细胞(B16-Luc)及B16F10H2Kb-/-细胞(B16-H2Kb-)。用control shRNA或是M6PR shRNA转染B16-H2Kb-细胞,分别建立其肿瘤小鼠模型,分别给与不同治疗方案,采用直接测量肿瘤大小以及活体成像技术动态监测肿瘤进展。
2.采用Real-time PCR和Western blotting方法检测体内、外经TAX、DOX化疗后B16F10、4T1、U266肿瘤细胞M6PR mRNA以及M6PR总蛋白和膜蛋白表达情况。应用免疫组化和Western blotting方法检测上述肿瘤细胞内M6PR主要配体IGF-II水平的变化,探索化疗上调肿瘤细胞表面M6PR的潜在机制。应用激光共聚焦显微镜观察化疗药物对肿瘤细胞自噬现象的影响。通过自噬抑制剂3-MA或atg5siRNA下调自噬以及通过自噬诱导剂Rapamycin上调自噬,应用流式细胞仪和共聚焦显微镜观察化疗对M6PR在肿瘤细胞内的分布情况。
结果
1.免疫治疗联合化疗的抗肿瘤效应
在MC38结肠癌小鼠模型中,与无治疗模型对照组相比,单一p53DC疫苗免疫治疗延缓了肿瘤的进展(P<0.05),单一TAX化疗也延缓了肿瘤的生长,但是治疗一经停止肿瘤迅速进展。与单一治疗相比,免疫治疗联合化疗显著的抑制了肿瘤的生长(P<0.05)。在TUBO乳腺癌小鼠模型中,与无治疗模型对照组相比,单一TAX化疗没有显著的抗肿瘤作用(P>0.05),单一Neu DC疫苗有轻微延缓肿瘤生长的作用(P>0.05)。与单一治疗相比,DC疫苗联合TAX治疗产生了显著的抗肿瘤效果(P<0.05)。在EG-7淋巴瘤小鼠模型中,与无治疗模型对照组相比,单一过继性T细胞免疫治疗或是TAX化疗均导致肿瘤缩小(P<0.05)。与单一治疗相比,联合治疗的抗肿瘤效应显著增强(P<0.05)。
2.化疗对肿瘤细胞表面M6PR的影响
(1)小鼠B16F10恶性黑色素瘤、4T1乳腺癌以及人多发性骨髓瘤8226、929、U266多种肿瘤细胞体外经化疗后细胞表面M6PR均上调性表达(P<0.05)。上述肿瘤细胞经化疗后摄取颗粒酶B也显著增加(P<0.05)。在B16F10恶性黑色素瘤、4T1乳腺癌小鼠模型中,TAX给药48小时后,免疫组化显示肿瘤组织M6PR表达显著性上调(P<0.05)。在给药后72小时,M6PR仍保持较高状态,在给药后5天其恢复到治疗前水平。在U266人多发性骨髓瘤裸鼠模型中,经DOX治疗后M6PR发生同样的变化。
(2)在B16F10荷瘤小鼠,与无治疗对照相比,单一Pme1-1CTLs或是TAX显著的抑制了肿瘤的生长,但是停止治疗后一周肿瘤继续增长。TAX联合T细胞治疗抗肿瘤效应显著增强(P<0.05)。T细胞输入2天之后给与TAX出现上述增强效应；而T细胞输入5天之前给与TAX,未观察到增强效应。
3.M6PR在化疗联合免疫治疗的抗肿瘤效应中的作用
(1)在转染了control shRNA的B16F10荷瘤小鼠中,与单一治疗相比,TAX联合Pme1-1CTL治疗抗肿瘤效应显著增强(P<0.05)。在转染了M6PR shRNA的荷瘤小鼠中,联合治疗未显示出增强作用(P>0.05)。
(2)在B16F10M6PR shRNA Kb荷瘤小鼠中,与未治疗对照相比,单一Trp2180-188CTLs未显示抗肿瘤活性(P>0.05)。与单一TAX化疗相比,联合治疗未显示出增强作用(P>0.05)。在B16F10control shRNA Kb荷瘤小鼠中,联合治疗也未显示出增强作用(P>0.05)。
(3)在B16F10-Luc(左侧肋腹)、control shRNA Kb"(右侧肋腹)双侧肿瘤小鼠模型中,针对B16F10-Luc肿瘤,联合治疗比单一免疫治疗或化疗显示出增强的抗肿瘤效应(P<0.05)；针对control shRNA Kb肿瘤,联合治疗未显示出增强作用(P>0.05)。在B16-Luc与control shRNA Kb-混合肿瘤模型中,与单一治疗相比,联合治疗导致肿瘤总体积显著缩小(P<0.05)。应用活体成像技术监测肿瘤组织中的B16F10-Luc细胞,联合治疗比单一免疫治疗或化疗显示出增强的抗肿瘤效应(P<0.05)。在B16-Luc与M6PR shRNA Kb-混合肿瘤模型中,与单一治疗相比,联合治疗未导致肿瘤总体积缩小(P>0.05)。应用活体成像技术监测肿瘤组织中的B16F10-Luc细胞,联合治疗比单一免疫治疗或化疗显示出增强的抗肿瘤效应(P<0.05)。
4.化疗对肿瘤细胞内M6PR合成、讲解以及再分布的影响(1)Real-time PCR结果显示,在M6PR mRNA表达水平上,化疗药物对B16F10、4T1和EL-4肿瘤细胞没有显著影响(P>0.05)。流式细胞分析数据显示,B16F10或是4T1肿瘤细胞经过TAX处理后,细胞表面上的M6PR被上调表达(P<0.05),细胞内M6PR总蛋白表达水平没有发生变化(P>0.05)。Western blotting结果显示,用TAX处理B16F10细胞或是用DOX处理EL-4、U266细胞后,M6PR总蛋白表达水平没有明显变化(P>0.05), M6PR膜蛋白水平显著增加(P<0.05)。
(2)激光共聚焦显微镜结果显示,在U266肿瘤细胞内化疗前M6PR集中在细胞浆内,而化疗后其主要定位于细胞膜；在多发性骨髓瘤患者骨髓切片中,治疗前只有20%的肿瘤细胞出现M6PR在细胞膜上的聚集现象,化疗后3天该比例增至50%以上(P<0.05)。
5.自噬对肿瘤细胞内M6PR再分布的影响
(1)流式细胞分析结果显示,经TAX预处理的B16F10细胞体外与重组IGF-Ⅱ共同孵育,细胞表面M6PR上调表达的能力缺失,细胞摄取颗粒酶B的能力也明显下降(P<0.05)。Western blotting结果显示,化疗药物体外对4T1、EL4、B16F10三种肿瘤细胞内IGF-Ⅱ表达水平没有显著作用(P>0.05)；4T1和B16F10荷瘤小鼠经TAX体内处理后,肿瘤组织中IGF-Ⅱ水平显著增加(P<0.05)。
(2)激光共聚焦显微镜结果显示,应用TAX、CIS、DOX处理肿瘤细胞后,自噬被迅速诱导。应用3-MA抑制自噬,DOX原先诱导的U266细胞表面M6PR的上调表达能力明显下降(P<0.05)；经过TAX处理后的B16F10细胞也出现此现象。应用atg5siRNA转染B16F10细胞下调自噬,TAX原先诱导的细胞膜M6PR的上调性表达现象显著下降(P<0.05)。应用Rapamycin诱导自噬,肿瘤细胞表面的M6PR明显增加(P<0.05)。用LC3-GFP转染B16F10肿瘤细胞,未经化疗处理的细胞没有观察到M6PR和LC3的共定位；细胞经TAX处理之后,更容易观察到自噬小体和M6PR的共定位现象。
结论
化疗可以增强CTL免疫治疗的效果,而该效应与M6PR介导的细胞内吞相关。化疗后肿瘤细胞表面M6PR的短暂诱导介导了化疗联合免疫治疗的旁观者效应,有利于二者产生协同作用。该作用与化疗诱导的自噬相关,而与肿瘤细胞内的IGF-Ⅱ水平无关。
Objective
1. To confirm the potentiation of the antitumor effects of immunotherapy in combination with chemotherapy by the investigation of different kinds of tumors established in mice. To test the effect of chemotherapy on M6PR in tumor cells by the treatment of B16F10,4T1or U266tumor cells in vitro and their tumors established in mice in vivo with chemotherapy. To test the role of M6PR in the combined therapy in vivo wild-type (H2Kb+/+) B16F10cells expressing luciferase (B16-Luc) and B16F10H2Kb-/-cells (B16-H2Kb-) were used. B16-H2Kb-cells were transfected with control or MPR shRNA and their tumors established in mice were treated with different therapy.
2. To investigate the mechanism of MPR up-regulation by chemotherapy through detecting the mpr mRNA and its protein expression in B16F10,4T1or U266cells in vitro and their tumors established in mice in vivo with chemotherapy. To study the association between MPR up-regulation and the expression of IGF-Ⅱ in tumor cells treated with chemotherapy. To test the in tumor cells induced by chemotherapy in vitro. To test the hypothesis of potentiating antitumor effects of immunotherapy combined with chemotherapy through investigating the re-distribution of M6PR in tumor cells by the up-regulation or down-regulation of autophagy.
Methods
1. The expression of M6PR on the surface of B16F10,4T1or U266tumor cells after chemotherapy was evaluated by flow cytometry. The M6PR protein levels in B16F10,4T1or U266tumors established in mice after chemotherapy were evaluated by Immunohistochemistry. wild-type (H2Kb+/+) B16F10cells expressing luciferase (B16-Luc) and B16F10H2Kb-/-cells (B16-H2Kb-) were used. B16-H2Kb-cells were transfected with control or MPR shRNA and their tumors established in mice were treated with different therapy. Tumor growth was monitored three times a week by caliper measurement and twice a week by in vivo imaging.
2. The mpr mRNA level in B16F10,4T1or U266cells in vitro and in vivo after chemotherapy was evaluated by Real-time PCR. The total M6PR protein and membrane fractions in these tumor cells were detected by Western blotting. The IGF-II protein level in tumor cells treated with chemotherapy was evaluated by Western blotting in order to study the mechanism of MPR up-regulation by chemotherapy. The autophagy in tumor cells induced by chemotherapy was evaluated by confocal microscopy. The re-distribution of M6PR in tumor cells after chemotherapy was detected using confocal microscopy and flow cytometry through the blockade of autophagy with either its inhibitor3MA or down-regulating atg5and through the up-regulation of autophagy with Rapamycin.
Results
1. The antitumor effect of immunotherapy combined with chemotherapy In MC38colon carcinoma models, Vaccination of mice with DCs transduced with adenovirus containing full-length mouse wild-type p53(Ad-p53) resulted in a substantial delay in tumor progression compared with no treatment (P<0.05). Treatment of mice with TAX alone delayed tumor growth, but tumor progression resumed soon after the treatment was discontinued. The combination of TAX and the DC vaccine potently suppressed tumor growth compared with either immunotherapy or chemotherapy alone (P<0.05). In TUBO breast carcinoma models, single TAX had very little antitumor activity and vaccination alone only slightly delayed tumor growth compared with no treatment (P>0.05). The combination of the DC vaccine with TAX treatment resulted in a substantial antitumor effect in this model as well (P<0.05).In EG-7lymphoma models, T cells or TAX alone caused a decrease in tumor growth compared with no treatment (P<0.05). This effect was substantially more pronounced when T cell transfer and TAX administration were combined (P<0.05).
2. The effect of chemotherapy on M6PR on tumor cell surface
(1) Several mouse (B16F10melanoma,4T1mammary carcinoma) and human multiple myeloma (8226, H929, U266) tumor cell lines were used to test the effects of chemotherapy on the expression of MPR. Different chemotherapeutic agents caused substantial and similar up-regulation of MPR expression in vitro in all tested mouse and human tumor cell lines (P<0.05). Chemotherapy also increased granzyme B (GrzB) penetration into cells (P<0.05).In B16F10,4T1tumor models significant (P<0.05) up-regulation of MPR expression was detected48hr after the injection of TAX using immunohistochemistry. It remained elevated for another24hr and then returned to the pre-treatment level within5days after injection. It also happened in U266tumors in nude mice treated with DOX.
(2) In B16F10tumor bearing mice, administration of either Pmel-1CTLs or TAX alone substantially delayed tumor growth, which however, resumed one week after the treatment. When TAX was combined with T-cell therapy, a significant (P<0.05) potentiating effect was observed. However, this effect was seen only if TAX was administered two days after T cells. When TAX was injected5days prior to T-cell administration, no increased antitumor effect was observed.
3. The role of M6PR in the effect of immunotherapy combined with chemotherapy
(1) In B16F10control shRNA tumor bearing mice, Pmel-1CTLs combined with TAX resulted in an increased antitumor effect compared with single therapy (P<0.05). In B16F10M6PR shRNA tumor bearing mice, no increased antitumor effect was observed in combination therapy (P>0.05).
(2) In B16F10M6PR shRNA Kb-tumor bearing mice, single Trp2180-188CTLs did not show any antitumor effect compared with no treatment (P>0.05). No increased antitumor effect was observed in combination therapy compared with single TAX (.P>0.05). In B16F10control shRNA Kb" tumor bearing mice, no increased antitumor effect was observed in combination therapy (P>0.05).
(3) B16-Luc and B16-control shRNA Kb-tumors were established in the opposite flanks (B16-Luc-left flank; B16-control shRNA Kb--right flank) of the same mouse. Significant (P<0.05) potentiation of the antitumor effects of combined TAX and CTLs was observed only in the flank with B16-Luc tumor but not with B16-control shRNA Kb" tumors. In the B16-Luc mixed with control shRNA Kb-tumor bearing mice, combining TAX and CTLs resulted in a significantly (P<0.05) greater antitumor effect than each of them separately. This was seen by monitoring tumor size with calipers and by in vivo imaging. In the B16-Luc mixed with M6PR shRNA Kb-tumor bearing mice, potentiation of the antitumor effect of combination therapy was not detected (P>0.05) while TAX and CTLs combined had potent antitumor activity against B16-Luc cells when these cells were monitored by in vivo imaging (P<0.05).
4. The effect of chemotherapy on MPR synthesis, degradation and re-distribution
(1) The result of Real-time PCR showed that no effect of chemotherapy drugs on mpr mRNA expression was found in B16F10,4T1and EL-4tumor cells (P>0.05). Treatment of B16F10or4T1tumor cells in vitro with TAX resulted in up-regulation of MPR on the cell surface (P>0.05). However, when the total amount of MPR was evaluated using Western blot, no effect of TAX or DOX on MPR was found. Similar results were obtained when cells were analyzed by flow cytometry after fixation and permeabilization prior to staining with anti-MPR antibody (P>0.05).In these tumor cell lines treated with TAX or DOX, chemotherapy induced substantial accumulation of MPR only in a membrane fraction (P<0.05).
(2) We evaluated MPR expression in human MM U266cells treated with DOX using confocal microscopy. Chemotherapy caused redistribution of MPR from a primarily cytoplasmic to a predominantly membrane localization of MPR. We assessed the proportion of MM cells with predominantly membrane localization of MPR using bone marrow slides from MM patietns. Prior to treatment only20%of the MM cells had such a characteristic, whereas after3days of high-dose chemotherapy this proportion increased to more than50%of all MM cells (P<0.05).
5. The effect of autophagy on the re-distribution of M6PR in tumor cells
(1) The flow data showed that incubation of B16F10tumor cells with recombinant IGF-Ⅱ led to the loss of the tumor cell's ability to up-regulate MPR expression on the surface in response to TAX. This was associated with loss of TAX-inducible up-regulation of GrzB uptake by tumor cells (P<0.05). The effect of chemotherapy on4T1, EL4. and B16F10tumor cell lines in vitro were evaluated by Western blotting. In all cases no decrease in IGF-II expression was detected (P>0.05). We also tested the in vivo effect of TAX treatment in4T1and B16F10tumor-bearing mice. Chemotherapy treatment caused a substantial increase in the level of IGF-2(P>0.05).
(2) Treatment of tumor cells with TAX, CIS, or DOX caused rapid induction of autophagy as determined by the appearance of autophagy-specific LC3punctae in treated cells by confocal microscopy. Inhibition of autophagy with3MA abrogated up-regulation of MPR on the surface of U266MM cells treated with DOX or B16F10cells treated with TAX (P<0.05). Transfection of B16F10cells with atg5siRNA completely abrogated the TAX-inducible increase in MPR expression (P<0.05). Rapamycin caused a substantial increase in MPR levels on the tumor cell surface (P<0.05). B16F10tumor cells were transfected with LC3-GFP. After treatment of the cells with TAX, LC3punctae became easily visualized by confocal microscopy. When untreated cells were stained with MPR antibody, no co-localization of MPR and LC3were seen. In contrast, after TAX, co-localization of autophagosomes and MPR was readily detectable.
Conclusion
Cancer immunotherapy in combination with chemotherapy may produce an increased antitumor effect. The antitumor effect of CTL is associated with endocytosis induced by M6PR. Chemotherapy combined with immunotherapy results in bystander killing of tumor cells without the need for antigen recognition and this effect was mediated by MPR. Chemotherapy dose not induce MPR synthesis or inhibit its degradation. Changes in IGF-2levels caused by chemotherapy were not associated with up-regulation of MPR on the tumor cell surface. Chemotherapy-inducible autophagy causes up-regulation of MPR on tumor cell surface.
引文
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