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

Licia Rivoltini, Marina Radrizzani, Paola Accornero, Paola Squarcina, Claudia Chiodoni, Arabella Mazzocchi, Chiara Castelli, Paolo Tarsini, Vincenzo Viggiano, Filiberto Belli, Mario P. Colombo, Giorgio Parmiani

Research output: Contribution to journalArticlepeer-review

Abstract

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 Th1 clones. Nevertheless, antimelanoma CTL clones resist apoptosis mediated by FasL 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.

Original languageEnglish
Pages (from-to)1220-1230
Number of pages11
JournalJournal of Immunology
Volume161
Issue number3
Publication statusPublished - Aug 1 1998

ASJC Scopus subject areas

  • Immunology

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