Format

Send to

Choose Destination
Cancer Discov. 2019 Jun 11. doi: 10.1158/2159-8290.CD-19-0074. [Epub ahead of print]

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

Author information

1
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
2
Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
3
The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
4
Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York.
5
Hospital del Mar, IMIM, Universitat Autònoma de Barcelona, Barcelona, Spain.
6
Division of Experimental Pathology, Department of Pathology, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
7
Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
8
First Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
9
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.
10
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
11
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. amaia.lujambio@mssm.edu.
#
Contributed equally

Abstract

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 immuno-therapies. 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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center