CD226(hi)CD8(+) T Cells Are a Prerequisite for Anti-TIGIT Immunotherapy

Abstract

Clinical trials are evaluating the efficacy of anti-TIGIT for use as single-agent therapy or in combination with programmed death 1 (PD-1)/programmed death-ligand 1 blockade. How and whether a TIGIT blockade will synergize with immunotherapies is not clear. Here, we show that CD226(lo)CD8(+) T cells accumulate at the tumor site and have an exhausted phenotype with impaired functionality. In contrast, CD226(hi)CD8(+) tumor-infiltrating T cells possess greater self-renewal capacity and responsiveness. Anti-TIGIT treatment selectively affects CD226(hi)CD8(+) T cells by promoting CD226 phosphorylation at tyrosine 322. CD226 agonist antibody-mediated activation of CD226 augments the effect of TIGIT blockade on CD8(+) T-cell responses. Finally, mFOLFIRINOX treatment, which increases CD226(hi)CD8(+) T cells in patients with pancreatic ductal adenocarcinoma, potentiates the effects of TIGIT or PD-1 blockade. Our results implicate CD226 as a predictive biomarker for cancer immunotherapy and suggest that increasing numbers of CD226(hi)CD8(+) T cells may improve responses to anti-TIGIT therapy.