Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response

Kvistborg, Pia, Philips, Daisy, Kelderman, Sander, Hageman, Lois, Ottensmeier, Christian, Joseph-Pietras, Deborah, Welters, Marij J.P., van der Burg, Sjoerd, Kapiteijn, Ellen, Michielin, Olivier, Romano, Emanuela, Linnemann, Carsten, Speiser, Daniel, Blank, Christian, Haanen, John B. and Schumacher, Ton N. (2014) Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Science Translational Medicine, 6 (254), [254RA128]. (doi:10.1126/scitranslmed.3008918). (PMID:25232180)

Abstract

Anti-CTLA-4 treatment improves the survival of patients with advanced-stage melanoma. However, although the anti-CTLA-4 antibody ipilimumab is now an approved treatment for patients with metastatic disease, it remains unknown by which mechanism it boosts tumor-specific T cell activity. In particular, it is unclear whether treatment amplifies previously induced T cell responses or whether it induces new tumor-specific T cell reactivities. Using a combination ultraviolet (UV)-induced peptide exchange and peptide-major histocompatibility complex (pMHC) combinatorial coding, we monitored immune reactivity against a panel of 145 melanoma-associated epitopes in a cohort of patients receiving anti-CTLA-4 treatment. Comparison of pre- and posttreatment T cell reactivities in peripheral blood mononuclear cell samples of 40 melanoma patients demonstrated that anti-CTLA-4 treatment induces a significant increase in the number of detectable melanoma-specific CD8 T cell responses (P = 0.0009). In striking contrast, the magnitude of both virus-specific and melanoma-specific T cell responses that were already detected before start of therapy remained unaltered by treatment (P = 0.74). The observation that anti-CTLA-4 treatment induces a significant number of newly detected T cell responses-but only infrequently boosts preexisting immune responses-provides strong evidence for anti-CTLA-4 therapy-enhanced T cell priming as a component of the clinical mode of action.

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