Transcriptome profiling identifies TIGIT as a marker of T-cell exhaustion in liver cancer

• Verfasst von: Ostroumov, Dmitrij [VerfasserIn]
• Verfasst von: Duong, Steven [VerfasserIn]
• Verfasst von: Wingerath, Jessica [VerfasserIn]
• Verfasst von: Woller, Norman [VerfasserIn]
• Verfasst von: Manns, Michael P. [VerfasserIn]
• Verfasst von: Timrott, Kai Fred Willi [VerfasserIn]
• Verfasst von: Kleine, Moritz [VerfasserIn]
• Verfasst von: Ramackers, Wolf-Rüdiger [VerfasserIn]
• Verfasst von: Rössler, Stephanie [VerfasserIn]
• Verfasst von: Nahnsen, Sven [VerfasserIn]
• Verfasst von: Dittrich-Breiholz, Oliver [VerfasserIn]
• Verfasst von: Eggert, Tobias [VerfasserIn]
• Verfasst von: Kühnel, Florian [VerfasserIn]
• Verfasst von: Wirth, Thomas [VerfasserIn]
• Titel: Transcriptome profiling identifies TIGIT as a marker of T-cell exhaustion in liver cancer
• Verf.angabe: 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
• Jahr: 2021
• Umfang: 20 S.
• Teil: volume:73
• Teil: year:2021
• Teil: number:4
• Teil: pages:1399-1418
• Teil: extent:20
• Fussnoten: First published: 27 July 2020 ; Gesehen am 08.06.2021
• Titel Quelle: Enthalten in: Hepatology
• Ort Quelle: New York [u.a.] : Wiley Interscience, 1981
• Jahr Quelle: 2021
• Band/Heft Quelle: 73(2021), 4, Seite 1399-1418
• ISSN Quelle: 1527-3350
• DOI: doi:10.1002/hep.31466
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1760015555

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.