TIGIT inhibits CD8+ T cell effector function during chronic viral infection and cancer (TUM7P.933)

• Published in: The Journal of immunology (1950) Vol. 192; no. 1_Supplement; pp. 203 - 203.15
• Main Authors: Grogan, Jane, Johnston, Robert, Comps-Agrar, Laetitia, Hackney, Jason, Yu, Xin, Huseni, Mahrukh, Yang, Yagai, Eaton, Dan, Park, Summer
• Format: Journal Article
• Language: English
• Published: 01.05.2014
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.192.Supp.203.15

Abstract Tumors constitute highly suppressive microenvironments in which infiltrating T cells are functionally suppressed by co-inhibitory receptor ligands. We identify T cell Immunoglobulin and ITIM domain (TIGIT) as a co-inhibitory receptor that critically limits CD8+ T cell responses to cancer and chronic infection. Expression of TIGIT was highly correlated with T cell infiltration in a broad range of solid tumors, and both human and murine tumor-infiltrating lymphocytes coordinately expressed TIGIT and PD-1, a key marker of T cell exhaustion. In mouse models of chronic viral infection and cancer, antibody blockades of TIGIT and PD-L1 synergistically and selectively enhanced CD8+ T cell effector function, resulting in significant viral clearance and tumor rejection respectively. Anti-TIGIT mediated anti-tumor immune responses were durable, as treated mice possessed antigen-specific and CD8+ T cell-dependent protection against tumor re-challenge. Strikingly, these effects were dependent on the activity of TIGIT’s complementary co-stimulatory receptor, CD226, whose dimerization and function was impaired by direct interaction with TIGIT in cis; and ablation of TIGIT was sufficient to enhance CD226 co-stimulation in CD8+ T cells. These results reveal a novel mechanism of action for co-inhibitory receptors and define a critical role for TIGIT as a regulator of anti-tumor and other chronic CD8+ T cell responses in vivo.