Transcriptome Profiling Identifies TIGIT as a Marker of T‐Cell Exhaustion in Liver Cancer

Abstract

PD‐1 checkpoint inhibition has shown promising results in patients with hepatocellular carcinoma, inducing objective responses in approximately 20% of the treated patients. The role of other co‐inhibitory molecules and their individual contribution to T cell dysfunction in liver cancer, however, remain largely elusive. Here we perform for the first time a comprehensive mRNA profiling of CD8 T cells in a murine model of autochthonous liver cancer by comparing the transcriptome of naive, functional effector and exhausted, tumor‐specific CD8 T cells. Subsequently we functionally validate the role of newly identified genes in T cell exhaustion. Our results reveal a unique transcriptome signature of exhausted T cells and demonstrate that upregulation of the inhibitory immune receptor TIGIT represents a hallmark in the process of T cell exhaustion in liver cancer. Compared to PD‐1, expression of TIGIT more reliably identified exhausted CD8 T cells at different stages of their differentiation. In combination with PD‐1 inhibition, targeting of TIGIT with antagonistic antibodies resulted in synergistic inhibition of liver cancer growth in immunocompetent mice. Finally, we demonstrate expression of TIGIT on tumor infiltrating CD8 T cells in tissue samples of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma and identify two subsets of patients based on differential expression of TIGIT on tumor‐specific T cells. Our transcriptome analysis provides a valuable resource for the identification of key pathways involved in T cell exhaustion in patients with liver cancer and identifies TIGIT as a potential target in checkpoint combination therapies.