The functionally exhausted CD8+ T cells expressing the immune checkpoint receptor TIGIT in gastric cancer patients had impaired glucose uptake due to the interaction between tumor-expressed CD155 and TIGIT. This metabolic impairment was reversed in vitro by TIGIT blockade or the addition of glucose. The combined blockade of TIGIT and PD-L1 in mice suppressed tumor progression and increased survival.
The T cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer (GC). We show that the percentage of CD8 T cells that are TIGIT+ was increased in GC patients compared to healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production and metabolism, all of which were rescued by glucose. In addition, GC tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-GC cell co-culture system, GC cells deprived CD8 T cells of glucose and impaired CD8 T cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In GC tumor cells, CD155 silencing increased T cell metabolism and IFNgamma production, whereas CD155 overexpression inhibited T cell metabolism and IFNgamma production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T cell reaction and improved survival in tumor bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T cell activation and improved survival in tumor bearing mice. Our results suggest that GC cells inhibit CD8 T cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer.