Abstract IA02: Next targets for immune checkpoint blockade in melanoma

Abstract

Abstract Multiple mechanisms of melanoma-induced immune escape contribute to the failure of T-cell responses to control tumor growth in humans. Many inhibitory pathways play a critical role in impeding T-cell responses to tumor antigens (TAs), including PD-1, the T-cell immunoglobulin and mucin-domain containing-protein 3 (Tim-3), and the T-cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors (IRs) are upregulated by TA-specific CD8+T cells in the tumor microenvironment (TME) while their respective ligands are expressed by antigen-presenting cells (APCs) and tumor cells. Circulating TA-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) that coexpress PD-1, TIGIT and Tim-3 exhibit different levels of T-cell dysfunction. Dysfunctional/exhausted CD8+ TILs are not totally inert and can exhibit cytolytic functions but are likely kept in check by multiple inhibitory pathways that can be targeted by immune checkpoint blockade. TIGIT is an attractive target for the next-generation immune checkpoint blockade for several reasons. First, it is highly expressed by the majority of CD8+ TILs together with PD-1. Second, the TIGIT ligands, CD155/PVR, and CD112, are highly expressed in the TME by melanoma cells and APCs. Third, dual PD-1/TIGIT blockade augments the expansion and function of human TA-specific CD8+ T cells in vitro and promotes tumor rejection in animal models. Fourth, TIGIT also acts in Tregs and NK cells to regulate antitumor immune responses. CD8+ TILs in melanoma and other solid tumors downregulate the costimulatory molecule DNAM-1/CD226, which competes with TIGIT for binding to the same ligands CD155 and CD112. Therefore, in addition to the TIGIT-mediated T-cell intrinsic inhibitory effects, the downregulation of CD226 expression by CD8+TILs in the TME also contributes to impede T-cell responses to melanoma. Collectively, our findings provide the rationale for dual PD-1/TIGIT blockade together with therapeutic strategies to counteract CD226 downregulation in the TME to improve the clinical benefits of single PD-1 blockade in patients with melanoma and other solid tumors. Citation Format: Joe-Marc Chauvin, Mignane Ka, Ornella Pagliano, Julien Foucade, Carmine Menna, Diwakar Davar, John Kirkwood, Vijay Kuchroo, Ana Anderson, Alan Korman, Hassane Zarour. Next targets for immune checkpoint blockade in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA02.