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Transcriptome Profiling Identifies TIGIT as a Marker of T‐Cell Exhaustion in Liver Cancer
Author(s) -
Ostroumov Dmitrij,
Duong Steven,
Wingerath Jessica,
Woller Norman,
Manns Michael P.,
Timrott Kai,
Kleine Moritz,
Ramackers Wolf,
Roessler Stephanie,
Nahnsen Sven,
Czemmel Stefan,
DittrichBreiholz Oliver,
Eggert Tobias,
Kühnel Florian,
Wirth Thomas C.
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31466
Subject(s) - tigit , transcriptome , cancer research , biology , cd8 , cytotoxic t cell , immune checkpoint , liver cancer , t cell , antibody , immune system , immunology , immunotherapy , hepatocellular carcinoma , gene expression , gene , genetics , in vitro
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.