肿瘤浸润免疫细胞对贲门癌根治术预后的影响
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摘要
目的
1.探讨肿瘤局部免疫细胞反应状态对贲门癌根治术预后的影响,以及细胞转化生长因子β1(TGF-β1)在肿瘤免疫中的可能作用。
2.随访调查汕头大学医学院附属肿瘤医院胸外科贲门癌根治术病人的治疗结果,分析影响贲门癌预后的临床病理因素。
方法
收集2000年10月至2002年10月间在汕头大学医学院附属肿瘤医院胸外科行根治性手术治疗的137例贲门癌患者的临床病理资料,对所有病人治疗结果进行至少5年的随访。Kaplan-meier法分析病人生存资料和影响预后的临床因素,显著性预后因素利用比例风险模型(Cox模型)进行多因素分析。免疫组化检测其中133例(剔除4例手术并发症死亡病人)贲门癌标本瘤内和瘤周CD3+细胞(总浸润性T淋巴细胞)、CD8+细胞(细胞毒性T细胞)、CD68+细胞(肿瘤相关巨噬细胞)、CD20+细胞(肿瘤浸润性B淋巴细胞)的密度以及贲门癌细胞TGF-β1的表达情况。肿瘤免疫学因素对临床治疗预后的影响进行单因素分析,其中显著性预后因素和各种临床病理参数进行Cox模型多因素分析,以筛选独立预后因素;T检验分析肿瘤细胞TGF-β1的表达强度对免疫细胞浸润密度的影响。
结果
1.单因素分析中:除了TNM分期(T分期,N分期,临床分期),其他对贲门癌根治术预后有显著性影响的临床病理因素包括性别、年龄、肿瘤大小(最长径)、有否术后化疗、清扫(送检)淋巴结总数、上下切缘与肿瘤距离(上、下瘤距)以及瘤内和瘤周CD3+细胞、CD68+细胞计数,瘤内CD8+细胞计数。其中,TNM分期、年龄和肿瘤大小与预后负相关,清扫(送检)淋巴结数目、上、下瘤距、术后化疗、瘤内和瘤周CD3+细胞、CD68+细胞计数,瘤内CD8+细胞计数与预后正相关,男性病人预后好于女性。
2.多因素分析:利用比例风险模型(Cox模型)对T分期,N分期,上瘤距、下瘤距、性别、有否术后化疗、送检淋巴结总数、瘤内CD8+细胞、CD3+细胞、CD68+细胞计数10个单因素分析中对预后有显著性影响的因素进行多因素分析,结果显示,T分期,N分期,性别、有否术后化疗、送检淋巴结总数、瘤内CD8+细胞计数、瘤内CD3+细胞计数为独立的预后影响因素。
3. TGF-β1对肿瘤局部免疫反应的影响:TGF-β1高、低表达组平均瘤内CD68+细胞数分别为: 9.7±6.83和12.2±7.07,差别有统计学意义(p=0.04)。TGF-β1高、低表达组平均瘤内CD3+细胞数分别为: 24.2±21.52和32.6±27.47,差别有统计学意义(p=0.05)。
结论
1.肿瘤浸润性T淋巴和肿瘤相关性巨噬细胞计数,对临床治疗预后有正面影响,是独立于TNM分期的预后影响因素,反映了病人抗肿瘤免疫的潜能。
2.随着TGF-β1表达增强,肿瘤浸润免疫细胞数量呈下降趋势,提示TGF-β1对宿主免疫系统有抑制作用,可能是肿瘤逃脱机体免疫监视的机制之一。
3.贲门癌外科临床方面:送检淋巴结总数与预后正相关,术后需重视标本解剖,保证有足够的送检淋巴结数,以免影响淋巴结分期的准确性;肿瘤切除范围应包括6cm以上正常食管和胃组织,以减少切缘阳性。术后辅助化疗可明显提高病人治疗效果,是今后贲门癌治疗的方向。
Objective
To evaluate the impacts of tumor infiltrating immune cells on long-term survivals of gastric cardia carcinoma and the significances of Transforming Growth Factor-β1(TGF-β1) in the interaction between immune system and tumor.
Methods
From October 2000 to October 2002, 137 patients with gastric cardia carcinoma underwent curative resection in Shantou University, Medical College, Cancer hospital. All patients were followed-up for at least 5 years. Detailed clinical and pathological data were collected. Intratumoral and peritumoral presence of various tumor-infiltrating immune cells, including CD3+、CD8+、CD68+、CD20+ cell, as well as the expression of tumor-deriving TGF-β1 were detected using immunohistochemistry in resection specimens from 133 patients(4 cases who died from severe surgical complications were excluded).
Univariate analysis was used to determine the prognostic value of infiltrating immune cell counts as well as other clinical and pathological parameters. For those statistically significant factors in univariate analysis, a multivariate analysis (Cox proportional hazard model) was performed to explore the independent prognostic factors.
The influence of TGF-β1 expressions on immune cell couts was evaluated using student T-test.
Results
1. univariate analysis:In univariate analysis, significant prognostic factors for Overall survival(OS) are: TNM stage(T stage, N stage, clinical stage),sex, age, tumor size, total number of examinated lymph nodes, distance from the upper and lower resection margins to macroscopic tumor borders(upper and lower resection margin distance). Intratumoral and peritumoral CD3+、CD68+cell counts and Intratumoral CD8+ cell counts. Among them, TNM stage, age, tumor size have reverse correlation to overall survival while number of examinated lymph nodes, extent of resection margins, Intratumoral and peritumoral CD3+、 CD68+cell counts and Intratumoral CD8+ cell counts have positive correlation to overall survival, Female patients have poor prognosis than male patients.
2. Multivariate analysis: 11 significant prognostic factors were chosen for multivariate analysis,they were T stage, N stage, sex, age,with or without chemotherapy,numbers of examinated lymph nodes, upper and lower resection margin distance, intratumoral CD3+、CD68+、CD8+cell counts l。The results shows that T stage, N stage, sex, with or without chemotherapy,numbers of examinated lymph nodes, intratumoral CD3+、CD68+cell counts are independent prognostic factors for Overall survival.
3. Impacts of TGF-β1 on local immune response: The means of intratumoral CD68+cell counts for low and high TGF-β1 groups were 12.2±7.07 and 9.7±6.83 respectively, and the difference was statistically significant. The means of intratumoral CD3+cell counts for low and high TGF-β1 groups were 32.6±27.47 and 24.2±21.52 respectively, and the difference was statistically significant. High level of TGF-β1 expression is correlative to poor treatment outcome, but the difference is not statistically significant(p=0.06)
Conclusions
1. The counts of TAM and tumor infiltrating T cell reflect the anti-caner potiental of immune system, and are independent prognostic factors.
2. TGF-β1 can reduce the number of tumor infiltrating immune cell, especially macrophages and tumor infiltrating T lymphocyted, which may be one of the mechanisms by which tumor escapes from immune surveillance.
3. The number of examinated lymph nodes is essentially needed for a correct N stage. Careful examination of the resection specimens for the lymph nodes is very important. Resection margin should include at least 6cm of normal esophagus and stomach to avoice tumor residence. Postoperative chemotherapy may improve the long-term survival and remains a better management for gastric cardia carcinoma.
1.探讨肿瘤局部免疫细胞反应状态对贲门癌根治术预后的影响,以及细胞转化生长因子β1(TGF-β1)在肿瘤免疫中的可能作用。
2.随访调查汕头大学医学院附属肿瘤医院胸外科贲门癌根治术病人的治疗结果,分析影响贲门癌预后的临床病理因素。
方法
收集2000年10月至2002年10月间在汕头大学医学院附属肿瘤医院胸外科行根治性手术治疗的137例贲门癌患者的临床病理资料,对所有病人治疗结果进行至少5年的随访。Kaplan-meier法分析病人生存资料和影响预后的临床因素,显著性预后因素利用比例风险模型(Cox模型)进行多因素分析。免疫组化检测其中133例(剔除4例手术并发症死亡病人)贲门癌标本瘤内和瘤周CD3+细胞(总浸润性T淋巴细胞)、CD8+细胞(细胞毒性T细胞)、CD68+细胞(肿瘤相关巨噬细胞)、CD20+细胞(肿瘤浸润性B淋巴细胞)的密度以及贲门癌细胞TGF-β1的表达情况。肿瘤免疫学因素对临床治疗预后的影响进行单因素分析,其中显著性预后因素和各种临床病理参数进行Cox模型多因素分析,以筛选独立预后因素;T检验分析肿瘤细胞TGF-β1的表达强度对免疫细胞浸润密度的影响。
结果
1.单因素分析中:除了TNM分期(T分期,N分期,临床分期),其他对贲门癌根治术预后有显著性影响的临床病理因素包括性别、年龄、肿瘤大小(最长径)、有否术后化疗、清扫(送检)淋巴结总数、上下切缘与肿瘤距离(上、下瘤距)以及瘤内和瘤周CD3+细胞、CD68+细胞计数,瘤内CD8+细胞计数。其中,TNM分期、年龄和肿瘤大小与预后负相关,清扫(送检)淋巴结数目、上、下瘤距、术后化疗、瘤内和瘤周CD3+细胞、CD68+细胞计数,瘤内CD8+细胞计数与预后正相关,男性病人预后好于女性。
2.多因素分析:利用比例风险模型(Cox模型)对T分期,N分期,上瘤距、下瘤距、性别、有否术后化疗、送检淋巴结总数、瘤内CD8+细胞、CD3+细胞、CD68+细胞计数10个单因素分析中对预后有显著性影响的因素进行多因素分析,结果显示,T分期,N分期,性别、有否术后化疗、送检淋巴结总数、瘤内CD8+细胞计数、瘤内CD3+细胞计数为独立的预后影响因素。
3. TGF-β1对肿瘤局部免疫反应的影响:TGF-β1高、低表达组平均瘤内CD68+细胞数分别为: 9.7±6.83和12.2±7.07,差别有统计学意义(p=0.04)。TGF-β1高、低表达组平均瘤内CD3+细胞数分别为: 24.2±21.52和32.6±27.47,差别有统计学意义(p=0.05)。
结论
1.肿瘤浸润性T淋巴和肿瘤相关性巨噬细胞计数,对临床治疗预后有正面影响,是独立于TNM分期的预后影响因素,反映了病人抗肿瘤免疫的潜能。
2.随着TGF-β1表达增强,肿瘤浸润免疫细胞数量呈下降趋势,提示TGF-β1对宿主免疫系统有抑制作用,可能是肿瘤逃脱机体免疫监视的机制之一。
3.贲门癌外科临床方面:送检淋巴结总数与预后正相关,术后需重视标本解剖,保证有足够的送检淋巴结数,以免影响淋巴结分期的准确性;肿瘤切除范围应包括6cm以上正常食管和胃组织,以减少切缘阳性。术后辅助化疗可明显提高病人治疗效果,是今后贲门癌治疗的方向。
Objective
To evaluate the impacts of tumor infiltrating immune cells on long-term survivals of gastric cardia carcinoma and the significances of Transforming Growth Factor-β1(TGF-β1) in the interaction between immune system and tumor.
Methods
From October 2000 to October 2002, 137 patients with gastric cardia carcinoma underwent curative resection in Shantou University, Medical College, Cancer hospital. All patients were followed-up for at least 5 years. Detailed clinical and pathological data were collected. Intratumoral and peritumoral presence of various tumor-infiltrating immune cells, including CD3+、CD8+、CD68+、CD20+ cell, as well as the expression of tumor-deriving TGF-β1 were detected using immunohistochemistry in resection specimens from 133 patients(4 cases who died from severe surgical complications were excluded).
Univariate analysis was used to determine the prognostic value of infiltrating immune cell counts as well as other clinical and pathological parameters. For those statistically significant factors in univariate analysis, a multivariate analysis (Cox proportional hazard model) was performed to explore the independent prognostic factors.
The influence of TGF-β1 expressions on immune cell couts was evaluated using student T-test.
Results
1. univariate analysis:In univariate analysis, significant prognostic factors for Overall survival(OS) are: TNM stage(T stage, N stage, clinical stage),sex, age, tumor size, total number of examinated lymph nodes, distance from the upper and lower resection margins to macroscopic tumor borders(upper and lower resection margin distance). Intratumoral and peritumoral CD3+、CD68+cell counts and Intratumoral CD8+ cell counts. Among them, TNM stage, age, tumor size have reverse correlation to overall survival while number of examinated lymph nodes, extent of resection margins, Intratumoral and peritumoral CD3+、 CD68+cell counts and Intratumoral CD8+ cell counts have positive correlation to overall survival, Female patients have poor prognosis than male patients.
2. Multivariate analysis: 11 significant prognostic factors were chosen for multivariate analysis,they were T stage, N stage, sex, age,with or without chemotherapy,numbers of examinated lymph nodes, upper and lower resection margin distance, intratumoral CD3+、CD68+、CD8+cell counts l。The results shows that T stage, N stage, sex, with or without chemotherapy,numbers of examinated lymph nodes, intratumoral CD3+、CD68+cell counts are independent prognostic factors for Overall survival.
3. Impacts of TGF-β1 on local immune response: The means of intratumoral CD68+cell counts for low and high TGF-β1 groups were 12.2±7.07 and 9.7±6.83 respectively, and the difference was statistically significant. The means of intratumoral CD3+cell counts for low and high TGF-β1 groups were 32.6±27.47 and 24.2±21.52 respectively, and the difference was statistically significant. High level of TGF-β1 expression is correlative to poor treatment outcome, but the difference is not statistically significant(p=0.06)
Conclusions
1. The counts of TAM and tumor infiltrating T cell reflect the anti-caner potiental of immune system, and are independent prognostic factors.
2. TGF-β1 can reduce the number of tumor infiltrating immune cell, especially macrophages and tumor infiltrating T lymphocyted, which may be one of the mechanisms by which tumor escapes from immune surveillance.
3. The number of examinated lymph nodes is essentially needed for a correct N stage. Careful examination of the resection specimens for the lymph nodes is very important. Resection margin should include at least 6cm of normal esophagus and stomach to avoice tumor residence. Postoperative chemotherapy may improve the long-term survival and remains a better management for gastric cardia carcinoma.
引文
[1] Gross L. Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res 1943;3:326–333.
[2] Foley EJ. Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res 1953;13:835–837.
[3] Prehn RT, Main JM. Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 1957;18:769–778.
[4] Boyse EA, Old LJ, Stockert E. Some further data on cytotoxic isoantibodies in the mouse. Ann NY Acad Sci 1962;99:574–587.
[5] Globerson A, Feldman M. Antigenic specificity of benzo(a)pyrene-induced sarcomas. J Natl Cancer Inst 1964;32:1229–1243.
[6] 6. Klein G, Sjogren HO, Klein E, et al. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 1960;20:1561–1572.
[7] Okada K, Nakashima M, Komuta K. Expression of tumor-associated membrane antigen, RCAS1, in human colorectal carcinomas and possible role in apoptosis of tumor-infiltrating lymphocytes. Mod Pathol. 2003 Jul;16(7):679-85.
[8] TomsováM, Melichar B, SedlákováPrognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma.Gynecol Oncol. 2008 Feb;108(2):415-20. Epub 2007 Nov 26
[9] Morris M, Platell C, Iacopetta B. Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-Fluorouracil chemotherapy.Clin Cancer Res. 2008 Mar 1;14(5):1413-7
[10] TomsováM, Melichar B, SedlákováI. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma.Gynecol Oncol. 2008 Feb;108(2):415-20. Epub 2007 Nov 26.
[11] Sharma P, Shen Y, Wen S. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma.
[12] Haanen JB, Baars A, Gomez R.Melanoma-specific tumor-infiltrating lymphocytes but notcirculating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients.Cancer Immunol Immunother. 2006 Apr;55(4):451-8. Epub 2005 Jul 21.
[13] Fukunaga A, Miyamoto M, Cho Y. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.Pancreas. 2004 Jan;28(1):e26-31
[14] Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. . N. Engl. J. Med. 2003;348:203–213.
[15] Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964.
[16] Yu P, Lee Y, Liu W, et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005;201:779–791.
[17] Turk MJ, Guevara-Patino JA, Rizzuto GA, et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004;200:771–782.
[18] Tawara I, Take Y, Uenaka A, et al. Sequential involvement of two distinct CD4+ regulatory T cells during the course of transplantable tumor growth and protection from 3-methylcholanthrene-induced tumorigenesis by CD25-depletion. Jpn J Cancer Res 2002;93:911–916.
[19] Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001;194:823–832.
[20] Steitz J, Bruck J, Lenz J, et al. Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 2001;61:8643–8646.
[21] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211–5218.
[22] Onizuka S, Tawara I, Shimizu J, et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res1999;59:3128–3133.
[23] Li J, Hu P, Khawli LA, et al. Complete regression of experimental solid tumors by combination LEC/chTNT-3 immunotherapy and CD25(+) T-cell depletion. Cancer Res 2003;63:8384–8392.
[24] Jones E, Dahm-Vicker M, Simon AK, et al. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002;2:1.
[25] Golgher D, Jones E, Powrie F, et al. Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 2002, 32: 3267–3275.
[26] Casares N, Arribillaga L, Sarobe P, et al. CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. J Immunol 2003;171:5931–5939.
[27] Siddiqui SA, Frigola X, Bonne-Annee S.Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.Clin Cancer Res. 2007 Apr 1;13(7):2075-81.
[28] Gualandris A., Rusnati M., Belleri M. et al. Basic fibroblast growth factor overexpression in endothelial cells: An autocrine mechanism for angiogenesis and angioproliferative diseases. CellGrowth & Differentiation, 19967, 147– 160.
[29] Iizasa H., Yoneyama H., Mukaida N. et al.. Exacerbation of granuloma formation in IL-1 receptor antagonist-deficient mice with impaired dendritic cell maturation associated with Th2 cytokine production.Journal of Immunology, 2005.174, 3273–3280.
[30] Wesa, A., & Galy, A. Increased production of proinflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand. BMC Immunology, 2002.3, 14.
[31] Song, X., Voronov, E., Dvorkin, T., Differential effects of IL-1 alpha and IL-1 beta on tumorigenicity patterns and invasiveness.Journal of Immunology, 2003.171, 6448–6456.
[32] He, Y. G., Mayhew, E., Mellon, J., Expression and possible function of IL-2 and IL-15 receptors on human uveal melanoma cells. Investigative Ophthalmology & Visual Science,2004. 45, 4240–4246.
[33] Tartour, E., Fossiez, F., Joyeux, I., Interleukin 17, a T-cell-derived cytokine, promotestumorigenicity of human cervical tumors in nude mice. Cancer Research, 1999.59:3698–3704.
[34] Guise, T. A., Kozlow, W. M., Heras-Herzig, A., et al. Molecular mechanisms ofbreast cancer metastases to bone. Clinical Breast Cancer, 2005, 5(Suppl), S46–S53
[35] Feijoo, E., Alfaro, C., Mazzolini, G., et al. Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. International Journal of Cancer, 2005, 116, 275–281.
[36] Sgadari, C., Angiolillo, A. L., Tosato, G. Inhibition ofangiogenesis by interleukin-12 is mediated by the interferoninducibleprotein 10. Blood,1996, 87, 3877–3882.
[37] Yue, F. Y., Dummer, R., Geertsen, R., Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. International Journal of Cancer,1997,71, 630–637.
[38] Benchetrit, F., Ciree, A., Vives, V., et al. Interleukin-17 inhibits tumor cellgrowth by means of a T-cell-dependent mechanism. Blood, 2002, 99,2114–2121.
[39] Yang, L., DeBusk, L. M., Fukuda, K., et al. Expansion of myeloid immunesuppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell,2004, 6, 409–421.
[40] Shurin, M. R., Yurkovetsky, Z. R., Tourkova, I. L., Inhibition of CD40 expression and CD40-mediated dendritic cell function by tumor-derived IL-10.International Journal of Cancer, 2002,101, 61–68.
[41] Roche WR. Mast cells and tumors. The specific enhancement of tumor proliferation in vitro. Am J Pathol 1985; 119: 57–64.
[42] Ortegel, J. W., E. D. Staren, L. P. Faber, W. H. Modulation of tumor-infiltrating lymphocyte cytolytic activity against human non-small cell lung cancer. Lung Cancer 2002,36:17.
[43]周维国,赵丽波,谢升伟等.喉癌局部免疫反应中细胞亚群与一月的作用及其相关性实用肿瘤学杂志,2001,15:257-260.
[44]苏敏;刘敏;田东萍等.广东南澳岛恶性肿瘤发病及居民饮食习惯的现况调查环境与职业医学2005, 2:312-316
[45] Ohno S, Inagawa H, Dhar D K, et al. The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients. AnticancerRes.2003 23:5015-22.
[46] Milasiene V, Stratilatovas E, Norkiene V. The importance of T-lymphocyte subsets on overall survival of colorectal and gastric cancer patients. Medicina (Kaunas). 2007;43(7):548-54.
[47]张汝刚方德康张大,等.为贲门癌的外科治疗结果(附1 832例分析)中华肿瘤学杂志,1998, 20:140-142.
[48] Roder JD, Bottcher K, Busch R, et a.l Classification of regionallymph node metastasis from gastric carcinoma. German Gastric CancerStudyGroup. Cancer, 1998, 82: 621-631.
[49] Ichikura T, Tomimastu S, Uefuji K, et a.l Evaluation of the New American Joint Committee on Cancer/ International Union against CancerClassification of lymph nodemetastasis from gastric carcinoma in comparison with the Japanese classification. Cancer, 1999, 86:553-558.
[50] BuntAM, Hogendoorn PC, van de Velde CJ, et a.l Lymph node staging standards in gastric cancer. J Clin Onco,l 1995, 13: 2309-2316.
[51] Roder JD, Bottcher K, Busch R, et a.l Classification of region lymph node metastasis from gastric carcinoma. German Gast Cancer Study Group. Cancer, 1998, 82: 621-631.
[52]张常华,何裕隆,詹文华等.贲门癌根治术后患者预后的多因素分析.中华胃肠外科学杂志2006,9:483-486.
[53]赵锡江,黄景陶,唐鹏等.贲门癌食管及胃切除范围的探讨.实用癌症杂志2007, 22: 57-59.
[54] Sastre J,Carcia-SaenzJA,Diaz-Rubio E. Chemotherapy for gastric CACCL World J Gastroenreml,2006,12: 204-213.
[55] Mahnke K, Bhardwaj R, Sorg C.Heterodimers of the calcium-binding proteins MRP8 and MRP14 are expressed on the surface of human monocytes upon adherence to fibronectin and collagen. Relation to TNF-alpha, IL-6, and superoxide production.J Leukoc Biol. 1995 57(1):63-71.
[56] Gabrilovich, D. I., Chen, H. L., Girgis, K. R., et al. (1996). Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Medicine, 2, 1096–1103.
[57] Toi, M., Kondo, S., Suzuki, H., et al.. Quantitative analysis of vascularendothelial growth factor in primary breast cancer. Cancer, 1996,77:1101–1106.
[58] Tartour, E., Fossiez, F., Joyeux, I.et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Research, 1999. 59:3698–3704.
[59] Gualandris, A., Rusnati, M., Belleri, M., Nelli, E. E., Bastaki, M., Molinari-Tosatti, M. P., et al. Basic fibroblast growth factor overexpression in endothelial cells: An autocrine mechanism for angiogenesis and angioproliferative diseases. Cell Growth & Differentiation, 1996:7, 147–160.
[60] Masson, V., de la Ballina, L. R.,Munaut, C. et al. Contribution of hostMMP-2 andMMP-9to promote tumor vascularization and invasion of malignant keratinocytes. FASEB Journal, 2005,19: 234–236.
[61] Gallo, O., Masini, E., Bianchi, B.et al (2002). Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma. Human Pathology, 33, 708–714.
[62] Leek, R. D., Lewis, C. E., Whitehouse, R.et al. Association of macrophage infiltrationwith angiogenesis and prognosis in invasive breast carcinoma.Cancer Research, 1996.56: 4625–4629.
[63] Hanada, T., Nakagawa, M., Emoto, A.et al. Prognostic value of tumor-associated macrophage count in human bladder cancer. International Journal of Urology, 2000,7: 263–269.
[64] Forssell, J., Oberg, A., Henriksson, M. L.,et al. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clinical Cancer Research, 2007,13:1472–1479.
[65] Ohno, S., Inagawa,H.,Dhar,D.K., Fujii, T.,Ueda, S., Tachibana, M.,et al. The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients.Anticancer Research, 2003,23: 5015–5022
[66] Pardoll DM, Topalian SL. The role of CD4+ T cellresponses in antitumor immunity. Curr Opin Immunol1998;10:588-94.
[67] Toes RE, Ossendorp F, Offringa R,Melief CJ. CD4 Tcells and their role in antitumor immune responses.JExpMed1999;189:753-6.
[68] HoWY, YeeC,Greenberg PD. Adoptive therapywithCD8(+) Tcells: it may get by with a littlehelp from itsfriends. JClin Invest 2002;110:1415-7.
[69] BevanMJ. Helping the CD8(+) T-cell response. NatRev Immunol 2004;4:595-602.
[70] Bourgeois C, Veiga-Fernandes H, Joret AM, et al.CD8 lethargy in the absence of CD4 help. Eur J Immunol 2002;32:2199-207.
[71] Kurts C, Carbone FR, Barnden M, et al. CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity.J Exp Med 1997;186:2057-62.
[72] Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.Science 2002;19:850-4.
[73] Greenberg PD. AdoptiveT cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol1991;49:281-355.
[74] Qin Z, BlankensteinT. CD4+ Tcell-mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFNg receptor expression by nonhematopoietic cells. Immunity 2000;12:677-86.
[75] Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531-62.
[76] Shevach EM.CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002; 2: 389-400.
[77] Wick, M., Dubey, P., Koeppen, H., Siegel, C.T., Fields, P.E., Chen, L., Bluestone, J.A., Schreiber, H., 1997.Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy. J. Exp. Med. 186, 229–238.
[78] Onizuka, S., Tawara, I., Shimizu, J., Sakaguchi, S., Fujita, T., Nakayama, E., 1999. Tumor rejection by in vivoadministration of anti-CD25 (interleukin-2 receptor _) monoclonal antibody. Cancer Res. 59, 3128–3133.
[79] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211- 8.
[80] Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergismof cytotoxicTlymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactivecytotoxic T lymphocyte responses. J Exp Med 2001; 194: 823-32.
[81] Whiteside, T. L., S. Miescher, J. Hurlimann, L. Moretta, V. von Fliedner. Separation, phenotyping and limiting dilution analysis of T-lymphocytes infiltrating human solid tumors. Int. J. 1986.Cancer 37:803.
[82] Rabinowich, H., R. Cohen, I. Bruderman, Z. Steiner, A. Klajman. Functional analysis of mononuclear cells infiltrating into tumors: lysis of autologous human tumor cells by cultured infiltrating lymphocytes. 1987. Cancer Res. 47:173.
[83] Halak, B. K., H. C. Maguire, Jr, E. C. Lattime. Tumor-induced interleukin-10 inhibits type 1 immune responses directed at a tumor antigen as well as a non-tumor antigen present at the tumor site. Cancer Res. 1999. 59:911
[84] Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatoryTcells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. EurJ Immunol 2004;34:336-44.
[85] SpornMB, PwbertsAB, wakefield LM, et al. Transforming growth factorβ:Biological function and chemical structure, Science,1986,233(4763):532-534.
[86] Pasche, B. Role of transforming growth factorβin cancer. J. Cell. Physiol. 2001 186:153.
[87] Merogi AJ, Marrogi AJ, Ramesh et al. R Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas. Hum Pathol. 1997 Mar;28(3):321-31.
[88] Wojtowicz-Praga S. Reversal of tumor-induced immunosu pression by TGF-βinhibitors[J]. Invest New Drugs,2003,(1):21-32.
[1] Gross L. Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res 1943;3:326–333.
[2] Foley EJ. Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res 1953;13:835–837.
[3] Prehn RT, Main JM. Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 1957;18:769–778.
[4] Boyse EA, Old LJ, Stockert E. Some further data on cytotoxic isoantibodies in the mouse. Ann NY Acad Sci 1962;99:574–587.
[5] Globerson A, Feldman M. Antigenic specificity of benzo(a)pyrene-induced sarcomas. J Natl Cancer Inst 1964;32:1229–1243.
[6] 6. Klein G, Sjogren HO, Klein E, et al. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 1960;20:1561–1572.
[7] Okada K, Nakashima M, Komuta K. Expression of tumor-associated membrane antigen, RCAS1, in human colorectal carcinomas and possible role in apoptosis of tumor-infiltrating lymphocytes. Mod Pathol. 2003 Jul;16(7):679-85.
[8] TomsováM, Melichar B, SedlákováPrognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma.Gynecol Oncol. 2008 Feb;108(2):415-20. Epub 2007 Nov 26
[9] Morris M, Platell C, Iacopetta B. Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-Fluorouracil chemotherapy.Clin Cancer Res. 2008 Mar 1;14(5):1413-7
[10] TomsováM, Melichar B, SedlákováI. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma.Gynecol Oncol. 2008 Feb;108(2):415-20. Epub 2007 Nov 26.
[11] Sharma P, Shen Y, Wen S. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma.
[12] Haanen JB, Baars A, Gomez R.Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients.Cancer Immunol Immunother. 2006 Apr;55(4):451-8. Epub 2005 Jul 21.
[13] Fukunaga A, Miyamoto M, Cho Y. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.Pancreas. 2004 Jan;28(1):e26-31
[14] Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. . N. Engl. J. Med. 2003;348:203–213.
[15] Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cellswithin human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964.
[16] Yu P, Lee Y, Liu W, et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005;201:779–791.
[17] Turk MJ, Guevara-Patino JA, Rizzuto GA, et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004;200:771–782.
[18] Tawara I, Take Y, Uenaka A, et al. Sequential involvement of two distinct CD4+ regulatory T cells during the course of transplantable tumor growth and protection from 3-methylcholanthrene-induced tumorigenesis by CD25-depletion. Jpn J Cancer Res 2002;93:911–916.
[19] Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001;194:823–832.
[20] Steitz J, Bruck J, Lenz J, et al. Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 2001;61:8643–8646.
[21] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211–5218.
[22] Onizuka S, Tawara I, Shimizu J, et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999;59:3128–3133.
[23] Li J, Hu P, Khawli LA, et al. Complete regression of experimental solid tumors by combination LEC/chTNT-3 immunotherapy and CD25(+) T-cell depletion. Cancer Res 2003;63:8384–8392.
[24] Jones E, Dahm-Vicker M, Simon AK, et al. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002;2:1.
[25] Golgher D, Jones E, Powrie F, et al. Depletion of CD25+ regulatory cells uncovers immuneresponses to shared murine tumor rejection antigens. Eur J Immunol 2002;32:3267–3275.
[26] Casares N, Arribillaga L, Sarobe P, et al. CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. J Immunol 2003;171:5931–5939.
[27] Siddiqui SA, Frigola X, Bonne-Annee S.Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.Clin Cancer Res. 2007 Apr 1;13(7):2075-81.
[28] Gualandris A., Rusnati M., Belleri M. et al. Basic fibroblast growth factor overexpression in endothelial cells: An autocrine mechanism for angiogenesis and angioproliferative diseases. CellGrowth & Differentiation, 19967, 147– 160.
[29] Iizasa H., Yoneyama H., Mukaida N. et al.. Exacerbation of granuloma formation in IL-1 receptor antagonist-deficient mice with impaired dendritic cell maturation associated with Th2 cytokine production.Journal of Immunology, 2005.174, 3273–3280.
[30] Wesa, A., & Galy, A. Increased production of proinflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand. BMC Immunology, 2002.3, 14.
[31] Song, X., Voronov, E., Dvorkin, T., Differential effects of IL-1 alpha and IL-1 beta on tumorigenicity patterns and invasiveness.Journal of Immunology, 2003.171, 6448–6456.
[32] He, Y. G., Mayhew, E., Mellon, J., Expression and possible function of IL-2 and IL-15 receptors on human uveal melanoma cells. Investigative Ophthalmology & Visual Science,2004. 45, 4240–4246.
[33] Tartour, E., Fossiez, F., Joyeux, I., Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Research, 1999.59:3698–3704.
[34] Guise, T. A., Kozlow, W. M., Heras-Herzig, A., et al. Molecular mechanisms ofbreast cancer metastases to bone. Clinical Breast Cancer, 2005, 5(Suppl), S46–S53
[35] Feijoo, E., Alfaro, C., Mazzolini, G., et al. Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. International Journal of Cancer, 2005, 116, 275–281.
[36] Sgadari, C., Angiolillo, A. L., Tosato, G. Inhibition ofangiogenesis by interleukin-12 is mediated by the interferoninducibleprotein 10. Blood,1996, 87, 3877–3882.
[37] Yue, F. Y., Dummer, R., Geertsen, R., Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. International Journal of Cancer,1997,71, 630–637.
[38] Benchetrit, F., Ciree, A., Vives, V., et al. Interleukin-17 inhibits tumor cellgrowth by means of a T-cell-dependent mechanism. Blood, 2002, 99,2114–2121.
[39] Masson, V., de la Ballina, L. R.,Munaut, et al. Contribution of hostMMP-2 andMMP-9 to promote tumor vascularization and invasion of malignant keratinocytes. FASEB Journal, 2005,19, 234–236.
[40] Yang, L., DeBusk, L. M., Fukuda, K., et al. Expansion of myeloid immunesuppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell,2004, 6, 409–421.
[41] Shurin, M. R., Yurkovetsky, Z. R., Tourkova, I. L., Inhibition of CD40 expression and CD40-mediated dendritic cell function by tumor-derived IL-10.International Journal of Cancer, 2002,101, 61–68.
[42] Nakano O, Sato M, Naito Y, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 2001;61:5132–5136.
[43] Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associatedantigen 4 blockade and depletion of CD25(+) regulatoryT cells in a17-1A MABtumor therapy reveals alternativepathways for suppression of autoreactive cytotoxic Tlymphocyte responses. J Exp Med 2001;194.3. 823–832.
[44] Steitz J, Bruck J, Lenz J, et al. Depletion of CD25(+)CD4(+) T cells and treatment with tyrosinase-relatedprotein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 2001;61:8643–8646.
[45] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211–5218.
[46] Jones E, Dahm-Vicker M, Simon AK, et al. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002;2:176-173
[47] Ladanyi A, Somlai B, Gilde K, Fejos Z, Gaudi I, Timar J. T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 2004;10: 521–30.
[48] Testi R, D'Ambrosio D, De Maria R, Santoni A. The CD69 receptor: a multipurpose cell-surface trigger for hematopoietic cells. Immunol Today 1994;15:479–83
[49] Alvaro, T., Lejeune, M., Salvado, M.T.,et al Outcome in Hodgkin’s lymphoma can be predicted from the presenceof accompanying cytotoxic and regulatory T cells. Clinical Cancer Research, 2005,11: 1467–1473.
[50] 9. Carreras, J., Lopez-Guillermo, A., Fox, B.C., Colomo, L., Martinez, A.,Roncador, G., Montserrat, E., Campo, E. & Banham, A.H. (2006)High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood, 2006, 108: 2957–2964.
[51] Lee, A.M., Clear, A.J., Calaminici, M., Davies, A.J., Jordan, S., Mac-Dougall, F., Matthews, J., Norton, A.J., Gribben, J.G., Lister, T.A. &Goff, L.K. (2006) Number of CD4+ cells and location of forkheadbox protein P3-positive cells in diagnostic follicular lymphomatissue microarrays correlates with outcome. Journal of ClinicalOncology, 24, 5052–5059.
[52] Dunn GP, Ikeda H, Bruce AT, Koebel C, Uppaluri R, Bui J, Chan R, Diamond M, White JM, Sheehan KC, et al. Immuol Res. 2005;32:231–246.
[53] Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, Ohuchi A, Ohuchi K, Shiiba K, Kurokawa Y, et al. Br J Cancer. 2004;91:1711–1717.
[54] Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al.Intraepithelial CD8+/tumor-infiltrating lymfocytes and a high CD8+/regulatory cell ratio are associated with favorable prognosis in ovariancancer. Proc Natl Acad Sci U S A 2005;102:18538–43.
[55]赵镇清,张熙曾等肺癌浸润淋巴细胞亚群测定及随访观察,肿瘤1999,52:173-177
[56] KHriaoka,MMiymaotoetal.ConeurrentnifiltrationbyCDS+TeellsandCD4+T cells15avafourbalePorngostieafetorinnon一small一Celll ungearenioma. British Joumal of Cancer, 2006,94:275一280.
[57]马建国,刘春霞,及和照,等.肾癌肿瘤浸润淋巴细胞免疫组化分析及其与肾癌愈后关系研究[ J ].张家口医学院学报, 2000, 17 (1) : 44 - 46.
[58] MovassaghM, SpatzA, Davoust J , et al. Selective accu2mulation ofmature DC - Lamp + dendritic cells in tumorsites is associated with efficient T - cell - mediated antitu2mor response and control of metastatic dissemination in melanoma Cancer Res, 2004, 64: 2192– 217
[2] Foley EJ. Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res 1953;13:835–837.
[3] Prehn RT, Main JM. Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 1957;18:769–778.
[4] Boyse EA, Old LJ, Stockert E. Some further data on cytotoxic isoantibodies in the mouse. Ann NY Acad Sci 1962;99:574–587.
[5] Globerson A, Feldman M. Antigenic specificity of benzo(a)pyrene-induced sarcomas. J Natl Cancer Inst 1964;32:1229–1243.
[6] 6. Klein G, Sjogren HO, Klein E, et al. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 1960;20:1561–1572.
[7] Okada K, Nakashima M, Komuta K. Expression of tumor-associated membrane antigen, RCAS1, in human colorectal carcinomas and possible role in apoptosis of tumor-infiltrating lymphocytes. Mod Pathol. 2003 Jul;16(7):679-85.
[8] TomsováM, Melichar B, SedlákováPrognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma.Gynecol Oncol. 2008 Feb;108(2):415-20. Epub 2007 Nov 26
[9] Morris M, Platell C, Iacopetta B. Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-Fluorouracil chemotherapy.Clin Cancer Res. 2008 Mar 1;14(5):1413-7
[10] TomsováM, Melichar B, SedlákováI. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma.Gynecol Oncol. 2008 Feb;108(2):415-20. Epub 2007 Nov 26.
[11] Sharma P, Shen Y, Wen S. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma.
[12] Haanen JB, Baars A, Gomez R.Melanoma-specific tumor-infiltrating lymphocytes but notcirculating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients.Cancer Immunol Immunother. 2006 Apr;55(4):451-8. Epub 2005 Jul 21.
[13] Fukunaga A, Miyamoto M, Cho Y. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.Pancreas. 2004 Jan;28(1):e26-31
[14] Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. . N. Engl. J. Med. 2003;348:203–213.
[15] Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964.
[16] Yu P, Lee Y, Liu W, et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005;201:779–791.
[17] Turk MJ, Guevara-Patino JA, Rizzuto GA, et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004;200:771–782.
[18] Tawara I, Take Y, Uenaka A, et al. Sequential involvement of two distinct CD4+ regulatory T cells during the course of transplantable tumor growth and protection from 3-methylcholanthrene-induced tumorigenesis by CD25-depletion. Jpn J Cancer Res 2002;93:911–916.
[19] Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001;194:823–832.
[20] Steitz J, Bruck J, Lenz J, et al. Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 2001;61:8643–8646.
[21] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211–5218.
[22] Onizuka S, Tawara I, Shimizu J, et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res1999;59:3128–3133.
[23] Li J, Hu P, Khawli LA, et al. Complete regression of experimental solid tumors by combination LEC/chTNT-3 immunotherapy and CD25(+) T-cell depletion. Cancer Res 2003;63:8384–8392.
[24] Jones E, Dahm-Vicker M, Simon AK, et al. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002;2:1.
[25] Golgher D, Jones E, Powrie F, et al. Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 2002, 32: 3267–3275.
[26] Casares N, Arribillaga L, Sarobe P, et al. CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. J Immunol 2003;171:5931–5939.
[27] Siddiqui SA, Frigola X, Bonne-Annee S.Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.Clin Cancer Res. 2007 Apr 1;13(7):2075-81.
[28] Gualandris A., Rusnati M., Belleri M. et al. Basic fibroblast growth factor overexpression in endothelial cells: An autocrine mechanism for angiogenesis and angioproliferative diseases. CellGrowth & Differentiation, 19967, 147– 160.
[29] Iizasa H., Yoneyama H., Mukaida N. et al.. Exacerbation of granuloma formation in IL-1 receptor antagonist-deficient mice with impaired dendritic cell maturation associated with Th2 cytokine production.Journal of Immunology, 2005.174, 3273–3280.
[30] Wesa, A., & Galy, A. Increased production of proinflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand. BMC Immunology, 2002.3, 14.
[31] Song, X., Voronov, E., Dvorkin, T., Differential effects of IL-1 alpha and IL-1 beta on tumorigenicity patterns and invasiveness.Journal of Immunology, 2003.171, 6448–6456.
[32] He, Y. G., Mayhew, E., Mellon, J., Expression and possible function of IL-2 and IL-15 receptors on human uveal melanoma cells. Investigative Ophthalmology & Visual Science,2004. 45, 4240–4246.
[33] Tartour, E., Fossiez, F., Joyeux, I., Interleukin 17, a T-cell-derived cytokine, promotestumorigenicity of human cervical tumors in nude mice. Cancer Research, 1999.59:3698–3704.
[34] Guise, T. A., Kozlow, W. M., Heras-Herzig, A., et al. Molecular mechanisms ofbreast cancer metastases to bone. Clinical Breast Cancer, 2005, 5(Suppl), S46–S53
[35] Feijoo, E., Alfaro, C., Mazzolini, G., et al. Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. International Journal of Cancer, 2005, 116, 275–281.
[36] Sgadari, C., Angiolillo, A. L., Tosato, G. Inhibition ofangiogenesis by interleukin-12 is mediated by the interferoninducibleprotein 10. Blood,1996, 87, 3877–3882.
[37] Yue, F. Y., Dummer, R., Geertsen, R., Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. International Journal of Cancer,1997,71, 630–637.
[38] Benchetrit, F., Ciree, A., Vives, V., et al. Interleukin-17 inhibits tumor cellgrowth by means of a T-cell-dependent mechanism. Blood, 2002, 99,2114–2121.
[39] Yang, L., DeBusk, L. M., Fukuda, K., et al. Expansion of myeloid immunesuppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell,2004, 6, 409–421.
[40] Shurin, M. R., Yurkovetsky, Z. R., Tourkova, I. L., Inhibition of CD40 expression and CD40-mediated dendritic cell function by tumor-derived IL-10.International Journal of Cancer, 2002,101, 61–68.
[41] Roche WR. Mast cells and tumors. The specific enhancement of tumor proliferation in vitro. Am J Pathol 1985; 119: 57–64.
[42] Ortegel, J. W., E. D. Staren, L. P. Faber, W. H. Modulation of tumor-infiltrating lymphocyte cytolytic activity against human non-small cell lung cancer. Lung Cancer 2002,36:17.
[43]周维国,赵丽波,谢升伟等.喉癌局部免疫反应中细胞亚群与一月的作用及其相关性实用肿瘤学杂志,2001,15:257-260.
[44]苏敏;刘敏;田东萍等.广东南澳岛恶性肿瘤发病及居民饮食习惯的现况调查环境与职业医学2005, 2:312-316
[45] Ohno S, Inagawa H, Dhar D K, et al. The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients. AnticancerRes.2003 23:5015-22.
[46] Milasiene V, Stratilatovas E, Norkiene V. The importance of T-lymphocyte subsets on overall survival of colorectal and gastric cancer patients. Medicina (Kaunas). 2007;43(7):548-54.
[47]张汝刚方德康张大,等.为贲门癌的外科治疗结果(附1 832例分析)中华肿瘤学杂志,1998, 20:140-142.
[48] Roder JD, Bottcher K, Busch R, et a.l Classification of regionallymph node metastasis from gastric carcinoma. German Gastric CancerStudyGroup. Cancer, 1998, 82: 621-631.
[49] Ichikura T, Tomimastu S, Uefuji K, et a.l Evaluation of the New American Joint Committee on Cancer/ International Union against CancerClassification of lymph nodemetastasis from gastric carcinoma in comparison with the Japanese classification. Cancer, 1999, 86:553-558.
[50] BuntAM, Hogendoorn PC, van de Velde CJ, et a.l Lymph node staging standards in gastric cancer. J Clin Onco,l 1995, 13: 2309-2316.
[51] Roder JD, Bottcher K, Busch R, et a.l Classification of region lymph node metastasis from gastric carcinoma. German Gast Cancer Study Group. Cancer, 1998, 82: 621-631.
[52]张常华,何裕隆,詹文华等.贲门癌根治术后患者预后的多因素分析.中华胃肠外科学杂志2006,9:483-486.
[53]赵锡江,黄景陶,唐鹏等.贲门癌食管及胃切除范围的探讨.实用癌症杂志2007, 22: 57-59.
[54] Sastre J,Carcia-SaenzJA,Diaz-Rubio E. Chemotherapy for gastric CACCL World J Gastroenreml,2006,12: 204-213.
[55] Mahnke K, Bhardwaj R, Sorg C.Heterodimers of the calcium-binding proteins MRP8 and MRP14 are expressed on the surface of human monocytes upon adherence to fibronectin and collagen. Relation to TNF-alpha, IL-6, and superoxide production.J Leukoc Biol. 1995 57(1):63-71.
[56] Gabrilovich, D. I., Chen, H. L., Girgis, K. R., et al. (1996). Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Medicine, 2, 1096–1103.
[57] Toi, M., Kondo, S., Suzuki, H., et al.. Quantitative analysis of vascularendothelial growth factor in primary breast cancer. Cancer, 1996,77:1101–1106.
[58] Tartour, E., Fossiez, F., Joyeux, I.et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Research, 1999. 59:3698–3704.
[59] Gualandris, A., Rusnati, M., Belleri, M., Nelli, E. E., Bastaki, M., Molinari-Tosatti, M. P., et al. Basic fibroblast growth factor overexpression in endothelial cells: An autocrine mechanism for angiogenesis and angioproliferative diseases. Cell Growth & Differentiation, 1996:7, 147–160.
[60] Masson, V., de la Ballina, L. R.,Munaut, C. et al. Contribution of hostMMP-2 andMMP-9to promote tumor vascularization and invasion of malignant keratinocytes. FASEB Journal, 2005,19: 234–236.
[61] Gallo, O., Masini, E., Bianchi, B.et al (2002). Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma. Human Pathology, 33, 708–714.
[62] Leek, R. D., Lewis, C. E., Whitehouse, R.et al. Association of macrophage infiltrationwith angiogenesis and prognosis in invasive breast carcinoma.Cancer Research, 1996.56: 4625–4629.
[63] Hanada, T., Nakagawa, M., Emoto, A.et al. Prognostic value of tumor-associated macrophage count in human bladder cancer. International Journal of Urology, 2000,7: 263–269.
[64] Forssell, J., Oberg, A., Henriksson, M. L.,et al. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clinical Cancer Research, 2007,13:1472–1479.
[65] Ohno, S., Inagawa,H.,Dhar,D.K., Fujii, T.,Ueda, S., Tachibana, M.,et al. The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients.Anticancer Research, 2003,23: 5015–5022
[66] Pardoll DM, Topalian SL. The role of CD4+ T cellresponses in antitumor immunity. Curr Opin Immunol1998;10:588-94.
[67] Toes RE, Ossendorp F, Offringa R,Melief CJ. CD4 Tcells and their role in antitumor immune responses.JExpMed1999;189:753-6.
[68] HoWY, YeeC,Greenberg PD. Adoptive therapywithCD8(+) Tcells: it may get by with a littlehelp from itsfriends. JClin Invest 2002;110:1415-7.
[69] BevanMJ. Helping the CD8(+) T-cell response. NatRev Immunol 2004;4:595-602.
[70] Bourgeois C, Veiga-Fernandes H, Joret AM, et al.CD8 lethargy in the absence of CD4 help. Eur J Immunol 2002;32:2199-207.
[71] Kurts C, Carbone FR, Barnden M, et al. CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity.J Exp Med 1997;186:2057-62.
[72] Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.Science 2002;19:850-4.
[73] Greenberg PD. AdoptiveT cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol1991;49:281-355.
[74] Qin Z, BlankensteinT. CD4+ Tcell-mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFNg receptor expression by nonhematopoietic cells. Immunity 2000;12:677-86.
[75] Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531-62.
[76] Shevach EM.CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002; 2: 389-400.
[77] Wick, M., Dubey, P., Koeppen, H., Siegel, C.T., Fields, P.E., Chen, L., Bluestone, J.A., Schreiber, H., 1997.Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy. J. Exp. Med. 186, 229–238.
[78] Onizuka, S., Tawara, I., Shimizu, J., Sakaguchi, S., Fujita, T., Nakayama, E., 1999. Tumor rejection by in vivoadministration of anti-CD25 (interleukin-2 receptor _) monoclonal antibody. Cancer Res. 59, 3128–3133.
[79] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211- 8.
[80] Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergismof cytotoxicTlymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactivecytotoxic T lymphocyte responses. J Exp Med 2001; 194: 823-32.
[81] Whiteside, T. L., S. Miescher, J. Hurlimann, L. Moretta, V. von Fliedner. Separation, phenotyping and limiting dilution analysis of T-lymphocytes infiltrating human solid tumors. Int. J. 1986.Cancer 37:803.
[82] Rabinowich, H., R. Cohen, I. Bruderman, Z. Steiner, A. Klajman. Functional analysis of mononuclear cells infiltrating into tumors: lysis of autologous human tumor cells by cultured infiltrating lymphocytes. 1987. Cancer Res. 47:173.
[83] Halak, B. K., H. C. Maguire, Jr, E. C. Lattime. Tumor-induced interleukin-10 inhibits type 1 immune responses directed at a tumor antigen as well as a non-tumor antigen present at the tumor site. Cancer Res. 1999. 59:911
[84] Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatoryTcells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. EurJ Immunol 2004;34:336-44.
[85] SpornMB, PwbertsAB, wakefield LM, et al. Transforming growth factorβ:Biological function and chemical structure, Science,1986,233(4763):532-534.
[86] Pasche, B. Role of transforming growth factorβin cancer. J. Cell. Physiol. 2001 186:153.
[87] Merogi AJ, Marrogi AJ, Ramesh et al. R Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas. Hum Pathol. 1997 Mar;28(3):321-31.
[88] Wojtowicz-Praga S. Reversal of tumor-induced immunosu pression by TGF-βinhibitors[J]. Invest New Drugs,2003,(1):21-32.
[1] Gross L. Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res 1943;3:326–333.
[2] Foley EJ. Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res 1953;13:835–837.
[3] Prehn RT, Main JM. Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 1957;18:769–778.
[4] Boyse EA, Old LJ, Stockert E. Some further data on cytotoxic isoantibodies in the mouse. Ann NY Acad Sci 1962;99:574–587.
[5] Globerson A, Feldman M. Antigenic specificity of benzo(a)pyrene-induced sarcomas. J Natl Cancer Inst 1964;32:1229–1243.
[6] 6. Klein G, Sjogren HO, Klein E, et al. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 1960;20:1561–1572.
[7] Okada K, Nakashima M, Komuta K. Expression of tumor-associated membrane antigen, RCAS1, in human colorectal carcinomas and possible role in apoptosis of tumor-infiltrating lymphocytes. Mod Pathol. 2003 Jul;16(7):679-85.
[8] TomsováM, Melichar B, SedlákováPrognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma.Gynecol Oncol. 2008 Feb;108(2):415-20. Epub 2007 Nov 26
[9] Morris M, Platell C, Iacopetta B. Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-Fluorouracil chemotherapy.Clin Cancer Res. 2008 Mar 1;14(5):1413-7
[10] TomsováM, Melichar B, SedlákováI. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma.Gynecol Oncol. 2008 Feb;108(2):415-20. Epub 2007 Nov 26.
[11] Sharma P, Shen Y, Wen S. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma.
[12] Haanen JB, Baars A, Gomez R.Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients.Cancer Immunol Immunother. 2006 Apr;55(4):451-8. Epub 2005 Jul 21.
[13] Fukunaga A, Miyamoto M, Cho Y. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.Pancreas. 2004 Jan;28(1):e26-31
[14] Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. . N. Engl. J. Med. 2003;348:203–213.
[15] Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cellswithin human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964.
[16] Yu P, Lee Y, Liu W, et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005;201:779–791.
[17] Turk MJ, Guevara-Patino JA, Rizzuto GA, et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004;200:771–782.
[18] Tawara I, Take Y, Uenaka A, et al. Sequential involvement of two distinct CD4+ regulatory T cells during the course of transplantable tumor growth and protection from 3-methylcholanthrene-induced tumorigenesis by CD25-depletion. Jpn J Cancer Res 2002;93:911–916.
[19] Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001;194:823–832.
[20] Steitz J, Bruck J, Lenz J, et al. Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 2001;61:8643–8646.
[21] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211–5218.
[22] Onizuka S, Tawara I, Shimizu J, et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999;59:3128–3133.
[23] Li J, Hu P, Khawli LA, et al. Complete regression of experimental solid tumors by combination LEC/chTNT-3 immunotherapy and CD25(+) T-cell depletion. Cancer Res 2003;63:8384–8392.
[24] Jones E, Dahm-Vicker M, Simon AK, et al. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002;2:1.
[25] Golgher D, Jones E, Powrie F, et al. Depletion of CD25+ regulatory cells uncovers immuneresponses to shared murine tumor rejection antigens. Eur J Immunol 2002;32:3267–3275.
[26] Casares N, Arribillaga L, Sarobe P, et al. CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. J Immunol 2003;171:5931–5939.
[27] Siddiqui SA, Frigola X, Bonne-Annee S.Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.Clin Cancer Res. 2007 Apr 1;13(7):2075-81.
[28] Gualandris A., Rusnati M., Belleri M. et al. Basic fibroblast growth factor overexpression in endothelial cells: An autocrine mechanism for angiogenesis and angioproliferative diseases. CellGrowth & Differentiation, 19967, 147– 160.
[29] Iizasa H., Yoneyama H., Mukaida N. et al.. Exacerbation of granuloma formation in IL-1 receptor antagonist-deficient mice with impaired dendritic cell maturation associated with Th2 cytokine production.Journal of Immunology, 2005.174, 3273–3280.
[30] Wesa, A., & Galy, A. Increased production of proinflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand. BMC Immunology, 2002.3, 14.
[31] Song, X., Voronov, E., Dvorkin, T., Differential effects of IL-1 alpha and IL-1 beta on tumorigenicity patterns and invasiveness.Journal of Immunology, 2003.171, 6448–6456.
[32] He, Y. G., Mayhew, E., Mellon, J., Expression and possible function of IL-2 and IL-15 receptors on human uveal melanoma cells. Investigative Ophthalmology & Visual Science,2004. 45, 4240–4246.
[33] Tartour, E., Fossiez, F., Joyeux, I., Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Research, 1999.59:3698–3704.
[34] Guise, T. A., Kozlow, W. M., Heras-Herzig, A., et al. Molecular mechanisms ofbreast cancer metastases to bone. Clinical Breast Cancer, 2005, 5(Suppl), S46–S53
[35] Feijoo, E., Alfaro, C., Mazzolini, G., et al. Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. International Journal of Cancer, 2005, 116, 275–281.
[36] Sgadari, C., Angiolillo, A. L., Tosato, G. Inhibition ofangiogenesis by interleukin-12 is mediated by the interferoninducibleprotein 10. Blood,1996, 87, 3877–3882.
[37] Yue, F. Y., Dummer, R., Geertsen, R., Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. International Journal of Cancer,1997,71, 630–637.
[38] Benchetrit, F., Ciree, A., Vives, V., et al. Interleukin-17 inhibits tumor cellgrowth by means of a T-cell-dependent mechanism. Blood, 2002, 99,2114–2121.
[39] Masson, V., de la Ballina, L. R.,Munaut, et al. Contribution of hostMMP-2 andMMP-9 to promote tumor vascularization and invasion of malignant keratinocytes. FASEB Journal, 2005,19, 234–236.
[40] Yang, L., DeBusk, L. M., Fukuda, K., et al. Expansion of myeloid immunesuppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell,2004, 6, 409–421.
[41] Shurin, M. R., Yurkovetsky, Z. R., Tourkova, I. L., Inhibition of CD40 expression and CD40-mediated dendritic cell function by tumor-derived IL-10.International Journal of Cancer, 2002,101, 61–68.
[42] Nakano O, Sato M, Naito Y, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 2001;61:5132–5136.
[43] Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associatedantigen 4 blockade and depletion of CD25(+) regulatoryT cells in a17-1A MABtumor therapy reveals alternativepathways for suppression of autoreactive cytotoxic Tlymphocyte responses. J Exp Med 2001;194.3. 823–832.
[44] Steitz J, Bruck J, Lenz J, et al. Depletion of CD25(+)CD4(+) T cells and treatment with tyrosinase-relatedprotein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 2001;61:8643–8646.
[45] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;163:5211–5218.
[46] Jones E, Dahm-Vicker M, Simon AK, et al. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002;2:176-173
[47] Ladanyi A, Somlai B, Gilde K, Fejos Z, Gaudi I, Timar J. T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 2004;10: 521–30.
[48] Testi R, D'Ambrosio D, De Maria R, Santoni A. The CD69 receptor: a multipurpose cell-surface trigger for hematopoietic cells. Immunol Today 1994;15:479–83
[49] Alvaro, T., Lejeune, M., Salvado, M.T.,et al Outcome in Hodgkin’s lymphoma can be predicted from the presenceof accompanying cytotoxic and regulatory T cells. Clinical Cancer Research, 2005,11: 1467–1473.
[50] 9. Carreras, J., Lopez-Guillermo, A., Fox, B.C., Colomo, L., Martinez, A.,Roncador, G., Montserrat, E., Campo, E. & Banham, A.H. (2006)High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood, 2006, 108: 2957–2964.
[51] Lee, A.M., Clear, A.J., Calaminici, M., Davies, A.J., Jordan, S., Mac-Dougall, F., Matthews, J., Norton, A.J., Gribben, J.G., Lister, T.A. &Goff, L.K. (2006) Number of CD4+ cells and location of forkheadbox protein P3-positive cells in diagnostic follicular lymphomatissue microarrays correlates with outcome. Journal of ClinicalOncology, 24, 5052–5059.
[52] Dunn GP, Ikeda H, Bruce AT, Koebel C, Uppaluri R, Bui J, Chan R, Diamond M, White JM, Sheehan KC, et al. Immuol Res. 2005;32:231–246.
[53] Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, Ohuchi A, Ohuchi K, Shiiba K, Kurokawa Y, et al. Br J Cancer. 2004;91:1711–1717.
[54] Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al.Intraepithelial CD8+/tumor-infiltrating lymfocytes and a high CD8+/regulatory cell ratio are associated with favorable prognosis in ovariancancer. Proc Natl Acad Sci U S A 2005;102:18538–43.
[55]赵镇清,张熙曾等肺癌浸润淋巴细胞亚群测定及随访观察,肿瘤1999,52:173-177
[56] KHriaoka,MMiymaotoetal.ConeurrentnifiltrationbyCDS+TeellsandCD4+T cells15avafourbalePorngostieafetorinnon一small一Celll ungearenioma. British Joumal of Cancer, 2006,94:275一280.
[57]马建国,刘春霞,及和照,等.肾癌肿瘤浸润淋巴细胞免疫组化分析及其与肾癌愈后关系研究[ J ].张家口医学院学报, 2000, 17 (1) : 44 - 46.
[58] MovassaghM, SpatzA, Davoust J , et al. Selective accu2mulation ofmature DC - Lamp + dendritic cells in tumorsites is associated with efficient T - cell - mediated antitu2mor response and control of metastatic dissemination in melanoma Cancer Res, 2004, 64: 2192– 217