Transcriptome Profiling Identifies TIGIT as a Marker of T-Cell Exhaustion in Liver Cancer
| Autor: | Stephanie Roessler, Florian Kühnel, Tobias Eggert, Michael P. Manns, Oliver Dittrich-Breiholz, Norman Woller, Moritz Kleine, Thomas Wirth, Sven Nahnsen, Kai Timrott, Dmitrij Ostroumov, Stefan Czemmel, Jessica Wingerath, Steven Duong, Wolf Ramackers |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Carcinoma Hepatocellular T cell Programmed Cell Death 1 Receptor Immune receptor Biology CD8-Positive T-Lymphocytes Transcriptome Cholangiocarcinoma 03 medical and health sciences Mice 0302 clinical medicine Lymphocytes Tumor-Infiltrating TIGIT Cell Line Tumor medicine Biomarkers Tumor Cytotoxic T cell Animals Humans Receptors Immunologic Immune Checkpoint Inhibitors Aged Hepatology Cluster of differentiation Gene Expression Profiling Liver Neoplasms Middle Aged medicine.disease Tumor Burden Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Treatment Outcome Bile Duct Neoplasms Cancer research 030211 gastroenterology & hepatology Drug Therapy Combination Female Liver cancer CD8 |
| Zdroj: | Hepatology (Baltimore, Md.)References. 73(4) |
| ISSN: | 1527-3350 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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