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Updated: Dec 13, 2025
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
Transcriptome Profiling Identifies TIGIT as a Marker of T-Cell Exhaustion in Liver Cancer
Dmitrij Ostroumov1, Steven Duong1, Jessica Wingerath1
1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
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.
Insights
T-cell exhaustion in liver cancer involves T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT). Targeting TIGIT with PD-1 inhibition synergistically inhibits liver cancer growth, offering a new therapeutic strategy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Programmed death 1 (PD-1) inhibition shows promise for hepatocellular carcinoma but doesn't fully address T-cell dysfunction.
- The roles of other coinhibitory molecules in liver cancer T-cell exhaustion are not well understood.
Purpose of the Study:
- To comprehensively profile mRNA in cluster of differentiation 8 (CD8) T cells during liver cancer progression.
- To identify novel targets for overcoming T-cell exhaustion in liver cancer.
Main Methods:
- Performed comprehensive mRNA profiling of CD8 T cells in a murine liver cancer model.
- Compared transcriptomes of naive, effector, and exhausted CD8 T cells.
- Functionally validated identified genes in T-cell exhaustion.
Main Results:
- Discovered a unique transcriptome signature for exhausted T cells.
- Identified T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) as a key marker of T-cell exhaustion in liver cancer.
- TIGIT expression reliably identified exhausted CD8 T cells and, when combined with PD-1 inhibition, synergistically reduced liver cancer growth.
Conclusions:
- Transcriptome analysis offers insights into T-cell exhaustion pathways in liver cancer.
- TIGIT is a promising target for combination immunotherapy in liver cancer.
- TIGIT expression in tumor-infiltrating CD8 T cells can stratify patients for targeted therapies.
