Human melanoma-reactive CD4+ and CD8+ CTL clones resist Fas ligand-induced apoptosis and use Fas/Fas ligand-independent mechanisms for tumor killing

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, He 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 land 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 Fast, triggered, on the contrary, by T cell activation with nonspecific stimuli such as PMA/ionomycin. Additionally, melanoma cells express significant levels of Fast (detectable on the cell surface only after treatment with metalloprotease inhibitors!, although to a lesser extent than professional immune cells such as Th1 clones. Nevertheless, antimelanoma CTL clones resist apoptosis mediated by Fast either in soluble form or expressed by Th1 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.