TIGIT mediated T cell exhaustion in cancer is dependent on TIGIT/CD226 interaction (TUM2P.907)

Abstract The generation of blocking antibodies against co-inhibitory receptors involved in T cell exhaustion is a recent key strategy for cancer immunotherapy. We have shown that co-blockade of TIGIT and PD-L1 results in tumor rejection by restoring the function of exhausted tumor-infiltrating CD8+ T cells. We were then interesting in deciphering the molecular mechanism of action of this anti-TIGIT blocking antibody. We hypothesized that TIGIT might inhibit a complementary co-activating receptor. Interestingly, TIGIT expression on tumor infiltrating CD8+ T cell was correlated with CD226, which binds a common receptor PVR. To better understand the relationship between these co-receptors, we utilized Time-resolved Fluorescence Resonance Energy (TR-FRET), a technology that allows for monitoring of cell surface protein interactions in real time. We showed that CD226 forms homodimers, and that co-expression of CD226 with TIGIT results in 1) the attenuation of CD226 self-association and 2) the formation of a TIGIT/CD226 complex in cis. Strikingly, anti-TIGIT antibody causes a significant decrease of the TIGIT/CD226 interaction. These observations indicate that the interaction of CD226 and TIGIT may play a central role in the antitumor effects of anti-TIGIT. Indeed, anti-CD226 antibodies blocked the ability of anti-PD-L1/anti-TIGIT to inhibit tumor growth in mice. Altogether, these results depict a close relationship between TIGIT and CD226 in CD8+ mediated T cell exhaustion.