Zippelius Alfred, Batard Pascal, Rubio-Godoy Verena, Bioley Gilles, Liénard Danielle, Lejeune Ferdy, Rimoldi Donata, Guillaume Philippe, Meidenbauer Norbert, Mackensen Andreas, Rufer Nathalie, Lubenow Norbert, Speiser Daniel, Cerottini Jean-Charles, Romero Pedro, Pittet Mikaël J
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research and Multidisciplinary Oncology Center, University Hospital (Centre Hospitalier Universitaire Vaudois), Lausanne, Switzerland.
Cancer Res. 2004 Apr 15;64(8):2865-73. doi: 10.1158/0008-5472.can-03-3066.
Although tumor-specific CD8 T-cell responses often develop in cancer patients, they rarely result in tumor eradication. We aimed at studying directly the functional efficacy of tumor-specific CD8 T cells at the site of immune attack. Tumor lesions in lymphoid and nonlymphoid tissues (metastatic lymph nodes and soft tissue/visceral metastases, respectively) were collected from stage III/IV melanoma patients and investigated for the presence and function of CD8 T cells specific for the tumor differentiation antigen Melan-A/MART-1. Comparative analysis was conducted with peripheral blood T cells. We provide evidence that in vivo-priming selects, within the available naive Melan-A/MART-1-specific CD8 T-cell repertoire, cells with high T-cell receptor avidity that can efficiently kill melanoma cells in vitro. In vivo, primed Melan-A/MART-1-specific CD8 T cells accumulate at high frequency in both lymphoid and nonlymphoid tumor lesions. Unexpectedly, however, whereas primed Melan-A/MART-1-specific CD8 T cells that circulate in the blood display robust inflammatory and cytotoxic functions, those that reside in tumor lesions (particularly in metastatic lymph nodes) are functionally tolerant. We show that both the lymph node and the tumor environments blunt T-cell effector functions and offer a rationale for the failure of tumor-specific responses to effectively counter tumor progression.
尽管肿瘤特异性CD8 T细胞反应常在癌症患者体内产生，但很少能导致肿瘤根除。我们旨在直接研究免疫攻击部位肿瘤特异性CD8 T细胞的功能效力。从III/IV期黑色素瘤患者中收集淋巴组织和非淋巴组织中的肿瘤病灶（分别为转移性淋巴结和软组织/内脏转移灶），并研究肿瘤分化抗原Melan-A/MART-1特异性CD8 T细胞的存在和功能。同时对外周血T细胞进行了比较分析。我们提供的证据表明，体内启动过程会在可用的初始Melan-A/MART-1特异性CD8 T细胞库中选择具有高T细胞受体亲和力的细胞，这些细胞在体外能够有效杀伤黑色素瘤细胞。在体内，启动后的Melan-A/MART-1特异性CD8 T细胞在淋巴和非淋巴肿瘤病灶中高频积聚。然而，出乎意料的是，尽管在血液中循环的启动后的Melan-A/MART-1特异性CD8 T细胞表现出强大的炎症和细胞毒性功能，但那些存在于肿瘤病灶（特别是转移性淋巴结）中的细胞却具有功能耐受性。我们表明，淋巴结和肿瘤环境都会削弱T细胞效应功能，并为肿瘤特异性反应无法有效对抗肿瘤进展提供了一个合理的解释。
