TIGIT Promotes Tumor Immune Escape via CD8⁺ T-cell Exhaustion

Tumor cells evade endogenous immune responses via upregulation of inhibitory receptors such as programmed cell death 1 (PD-1) and its ligand PD-L1 and exhaustion of infiltrating tumor-specific T cells. Reactivation of immune responses by blocking these inhibitory signals has achieved significant clinical success in certain types of cancer, prompting Johnston and colleagues to search for additional T-cell inhibitory receptors. Analysis of a tumor-associated T-cell–specific gene signature across a panel of various solid tumors revealed that expression of the co-inhibitory receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) was increased in CD8⁺ and CD4⁺ tumor-infiltrating lymphocytes (TIL) and was correlated with expression of PD-1, suggesting that TIGIT contributes to the regulation of exhausted TILs and antitumor immune responses. Consistent with this idea, co-inhibition of PD-L1 and TIGIT, but not either protein alone, led to tumor shrinkage in immune-competent murine tumor models and a protective antitumor response that prevented the growth of reinoculated tumor cells. Importantly, combined PD-L1 and TIGIT blockade was unable to prevent tumor formation in mice depleted of CD8⁺ T cells. Co-inhibition of PD-L1 and TIGIT enhanced proinflammatory cytokine production by CD8⁺, but not CD4⁺, T cells both in a tumor context and following chronic viral infection, suggesting that PD-1/PD-L1 and TIGIT synergistically inhibit CD8⁺ effector T-cell activity. Mechanistically, the antitumorigenic functions of TIGIT were dependent on CD226, TIGIT's complementary costimulatory receptor. Binding of TIGIT to CD226 on the cell surface prevented CD226 homodimerization and limited its activation, and CD226 blockade prevented the ability of anti-TIGIT antibody to enhance the function of CD8⁺ TILs. Together, these results highlight a role for TIGIT in suppressing chronic CD8⁺ T-cell responses and provide a rationale for cotargeting inhibitory receptors in the treatment of cancer and viral infections.

Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8⁺ T cell effector function. Cancer Cell 2014;26:923–37.

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