Transcriptome Profiling Identifies TIGIT as a Marker of T-Cell Exhaustion in Liver Cancer.
Hepatology, 2021/04;73(4):1399-1418.
Ostroumov D[1], Duong S[1], Wingerath J[1], Woller N[1], Manns MP[1], Timrott K[2], Kleine M[2], Ramackers W[2], Roessler S[3], Nahnsen S[4], Immunoglobulin And Immunoreceptor tyrosiCzemmel[4], Dittrich-Breiholz O[5], Eggert T[1], Kühnel F[1], Wirth TC[1]
Affiliations
PMID: 32716559DOI: 10.1002/hep.31466
Impact factor: 17.298
Abstract
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.
MeSH terms
Aged; Animals; Bile Duct Neoplasms; Biomarkers, Tumor; CD8-Positive T-Lymphocytes; Carcinoma, Hepatocellular; Cell Line, Tumor; Cholangiocarcinoma; Disease Models, Animal; Drug Therapy, Combination; Female; Gene Expression Profiling; Humans; Immune Checkpoint Inhibitors; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Mice; Mice, Inbred C57BL; Middle Aged; Programmed Cell Death 1 Receptor; Receptors, Immunologic; Transcriptome; Treatment Outcome; Tumor Burden
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