Rivoltini L, Radrizzani M, Accornero P, Squarcina P, Chiodoni C, Mazzocchi A, Castelli C, Tarsini P, Viggiano V, Belli F, Colombo M P, Parmiani G
Division of Experimental Oncology D, Istituto Nazionale Tumori, Milan, Italy.
J Immunol. 1998 Aug 1;161(3):1220-30.
Tumor cells have been shown recently to escape immune recognition by developing resistance to Fas-mediated apoptosis and acquiring expression of Fas ligand (FasL) molecule that they may use for eliminating activated Fas+ lymphocytes. In this study, we report that tumor-specific T lymphocytes isolated from tumor lesions by repeated in vitro TCR stimulation with relevant Ags (mostly represented by normal self proteins, such as MART-1/Melan A and gp100) can develop strategies for overcoming these escape mechanisms. Melanoma cells (and normal melanocytes) express heterogeneous levels of Fas molecule, but they result homogeneously resistant to Fas-induced apoptosis. However, CD4+ and CD8+ CTL clones kill melanoma cells through Fas/FasL-independent, granule-dependent lytic pathway. In these lymphocytes, Ag/MHC complex interaction with TCR does not lead to functional involvement of FasL, triggered, on the contrary, by T cell activation with nonspecific stimuli such as PMA/ionomycin. Additionally, melanoma cells express significant levels of FasL (detectable on the cell surface only after treatment with metalloprotease inhibitors), although to a lesser extent than professional immune cells such as Thl clones. Nevertheless, antimelanoma CTL clones resist apoptosis mediated by FasL either in soluble form or expressed by Thl lymphocytes or FasL+ melanoma cells. These results demonstrate that CD4+ and CD8+ antimelanoma T cell clones can be protected against Fas-dependent apoptosis, and thus be useful reagents of immunotherapeutic strategies aimed to potentiate tumor-specific T cell responses.
最近研究表明，肿瘤细胞可通过对Fas介导的凋亡产生抗性并获得Fas配体（FasL）分子的表达来逃避免疫识别，它们可能利用FasL分子清除活化的Fas+淋巴细胞。在本研究中，我们报告称，通过用相关抗原（主要由正常自身蛋白代表，如MART-1/黑色素A和gp100）进行反复体外TCR刺激，从肿瘤病变中分离出的肿瘤特异性T淋巴细胞能够制定克服这些逃逸机制的策略。黑色素瘤细胞（和正常黑素细胞）表达不同水平的Fas分子，但它们对Fas诱导的凋亡均具有抗性。然而，CD4+和CD8+CTL克隆通过不依赖Fas/FasL、依赖颗粒的裂解途径杀伤黑色素瘤细胞。在这些淋巴细胞中，抗原/MHC复合物与TCR的相互作用不会导致FasL的功能性参与，相反，FasL是由PMA/离子霉素等非特异性刺激激活T细胞所触发的。此外，黑色素瘤细胞表达显著水平的FasL（仅在用金属蛋白酶抑制剂处理后可在细胞表面检测到），尽管其表达水平低于Th1克隆等专业免疫细胞。尽管如此，抗黑色素瘤CTL克隆对FasL介导的凋亡具有抗性，无论是可溶性形式的FasL，还是由Th1淋巴细胞或FasL+黑色素瘤细胞表达的FasL。这些结果表明，CD4+和CD8+抗黑色素瘤T细胞克隆可免受Fas依赖性凋亡的影响，因此是旨在增强肿瘤特异性T细胞反应的免疫治疗策略的有用试剂。
