Abstract 459: Targeting TIGIT and PD-1 to increase the expansion and function of tumor antigen-specific CD8+ T cells in melanoma patients

Abstract

Abstract T-cell Immunoglobulin and ITIM Domain (TIGIT) is an inhibitory receptor expressed by activated T cells, regulatory T cells and NK cells. Here, we show that tumor antigen (TA)-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) upregulate TIGIT and most often co-express TIGIT and PD-1 in melanoma patients. CD8+ TILs downregulate CD226, supporting an imbalance of TIGIT/CD226 expression in metastatic melanoma. TIGIT is a marker of early T cell activation, which is further upregulated by T cells upon PD-1 blockade and by dysfunctional PD-1+Tim-3+ TA-specific CD8+ T cells. PD-1+TIGIT+, PD-1−TIGIT+ and PD-1+ TIGIT− CD8+ TILs exhibit similar functional capacities ex vivo, suggesting that TIGIT upregulation alone or together with PD-1 is not a marker of T cell dysfunction. However, in the presence of TIGIT ligand-expressing cells, TIGIT blockade adds to PD-1 blockade to increase the proliferation, cytokine production and degranulation of TA-specific CD8+ T cells and CD8+ TILs. Collectively, our findings show that TIGIT together with PD-1 regulate the expansion and function of TA-specific CD8+ T cells and CD8+TILs in melanoma patients. They also support the use of dual TIGIT and PD-1 blockade to stimulate potent antitumor CD8+ T cells responses in patients with advanced melanoma. Citation Format: Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Cindy Sanders, John M. Kirkwood, Tseng-hui T. Chen, Mark Maurer, Alan Korman, Hassane Zarour. Targeting TIGIT and PD-1 to increase the expansion and function of tumor antigen-specific CD8+ T cells in melanoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 459. doi:10.1158/1538-7445.AM2015-459