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

• Published in: Hepatology (Baltimore, Md.) Vol. 73; no. 4; pp. 1399 - 1418
• Main Authors: Ostroumov, Dmitrij, Duong, Steven, Wingerath, Jessica, Woller, Norman, Manns, Michael P., Timrott, Kai, Kleine, Moritz, Ramackers, Wolf, Roessler, Stephanie, Nahnsen, Sven, immunoglobulin and immunoreceptor tyrosiCzemmel, Dittrich‐Breiholz, Oliver, Eggert, Tobias, Kühnel, Florian, Wirth, Thomas C.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-04-2021
• Subjects: Aged; Animal models; Animals; Apoptosis; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - immunology; Bile Duct Neoplasms - pathology; Biomarkers, Tumor - genetics; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - pathology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell differentiation; Cell Line, Tumor; Cholangiocarcinoma; Cholangiocarcinoma - genetics; Cholangiocarcinoma - immunology; Cholangiocarcinoma - pathology; Disease Models, Animal; Drug Therapy, Combination; Female; Gene expression; Gene Expression Profiling - methods; Hepatocellular carcinoma; Hepatocytes; Hepatology; Humans; Immune Checkpoint Inhibitors - therapeutic use; Liver cancer; Liver diseases; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - immunology; Liver Neoplasms - pathology; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Male; Mice; Mice, Inbred C57BL; Middle Aged; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - genetics; Transcriptome; Transcriptomes; Treatment Outcome; Tumor Burden - drug effects; Tyrosine
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.31466

BACKGROUND AND AIMS
Programmed death 1 (PD‐1) checkpoint inhibition has shown promising results in patients with hepatocellular carcinoma, inducing objective responses in approximately 20% of treated patients. The roles of other coinhibitory molecules and their individual contributions to T‐cell dysfunction in liver cancer, however, remain largely elusive.
APPROACH AND RESULTS
We performed a comprehensive mRNA profiling of cluster of differentiation 8 (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 validated the role of identified genes in T‐cell exhaustion. Our results reveal a unique transcriptome signature of exhausted T cells and demonstrate that up‐regulation of the inhibitory immune receptor T‐cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibitor motif domains (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.
CONCLUSIONS
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.