β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma.

Autor:	Ruiz de Galarreta M; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Bresnahan E; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Molina-Sánchez P; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Lindblad KE; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York., Maier B; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Sia D; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Puigvehi M; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Hospital del Mar, IMIM, Universitat Autònoma de Barcelona, Barcelona, Spain., Miguela V; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Casanova-Acebes M; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Dhainaut M; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Villacorta-Martin C; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Singhi AD; Division of Experimental Pathology, Department of Pathology, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Moghe A; Division of Experimental Pathology, Department of Pathology, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., von Felden J; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; First Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Tal Grinspan L; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Wang S; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Kamphorst AO; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York., Monga SP; Division of Experimental Pathology, Department of Pathology, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Brown BD; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York., Villanueva A; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York., Llovet JM; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit and Pathology Department, IDIBAPS, Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., Merad M; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York., Lujambio A; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. amaia.lujambio@mssm.edu.; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2019 Aug; Vol. 9 (8), pp. 1124-1141. Date of Electronic Publication: 2019 Jun 11.
DOI:	10.1158/2159-8290.CD-19-0074
Abstrakt:	PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti-PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;Trp53 -/- HCCs led to T cell-mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;Trp53 -/- HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigen-expressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, β-catenin-driven tumors were resistant to anti-PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti-PD-1 and could represent a novel biomarker for HCC patient exclusion. SIGNIFICANCE: Determinants of response to anti-PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti-PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion. See related commentary by Berraondo et al., p. 1003 . This article is highlighted in the In This Issue feature, p. 983 . (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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