Transcriptome profiling identifies TIGIT as a marker of T-cell exhaustion in liver cancer
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 dys...
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| Hauptverfasser: | , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2021
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| In: |
Hepatology
Year: 2021, Jahrgang: 73, Heft: 4, Pages: 1399-1418 |
| ISSN: | 1527-3350 |
| DOI: | 10.1002/hep.31466 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/hep.31466 Verlag, lizenzpflichtig, Volltext: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31466 
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| Verfasserangaben: | Dmitrij Ostroumov, Steven Duong, Jessica Wingerath, Norman Woller, Michael P. Manns, Kai Timrott, Moritz Kleine, Wolf Ramackers, Stephanie Roessler, Sven Nahnsen, Oliver Dittrich-Breiholz, Tobias Eggert, Florian Kühnel, and Thomas C. Wirth |
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| 245 | 1 | 0 | |a Transcriptome profiling identifies TIGIT as a marker of T-cell exhaustion in liver cancer |c Dmitrij Ostroumov, Steven Duong, Jessica Wingerath, Norman Woller, Michael P. Manns, Kai Timrott, Moritz Kleine, Wolf Ramackers, Stephanie Roessler, Sven Nahnsen, Oliver Dittrich-Breiholz, Tobias Eggert, Florian Kühnel, and Thomas C. Wirth |
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| 520 | |a 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. | ||
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