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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: Ostroumov, Dmitrij (VerfasserIn) , Duong, Steven (VerfasserIn) , Wingerath, Jessica (VerfasserIn) , Woller, Norman (VerfasserIn) , Manns, Michael P. (VerfasserIn) , Timrott, Kai (VerfasserIn) , Kleine, Moritz (VerfasserIn) , Ramackers, Wolf-Rüdiger (VerfasserIn) , Rössler, Stephanie (VerfasserIn) , Nahnsen, Sven (VerfasserIn) , Dittrich-Breiholz, Oliver (VerfasserIn) , Eggert, Tobias (VerfasserIn) , Kühnel, Florian (VerfasserIn) , Wirth, Thomas (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2021
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
Volltext
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
Beschreibung
Zusammenfassung: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.
Beschreibung:First published: 27 July 2020
Gesehen am 08.06.2021
Beschreibung:Online Resource
ISSN:1527-3350
DOI:10.1002/hep.31466

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