beta-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma
(1) Ruiz de Galarreta M (2) Bresnahan E (3) Molina-Sanchez P (4) Lindblad KE (5) Maier B (6) Sia D (7) Puigvehi M (8) Miguela V (9) Casanova-Acebes M (10) Dhainaut M (11) Villacorta-Martin C (12) Singhi AD (13) Moghe A (14) von Felden J (15) Tal Grinspan L (16) Wang S (17) Kamphorst AO (18) Monga SP (19) Brown BD (20) Villanueva A (21) Llovet JM (22) Merad M (23) Lujambio A
(1) Ruiz de Galarreta M (2) Bresnahan E (3) Molina-Sanchez P (4) Lindblad KE (5) Maier B (6) Sia D (7) Puigvehi M (8) Miguela V (9) Casanova-Acebes M (10) Dhainaut M (11) Villacorta-Martin C (12) Singhi AD (13) Moghe A (14) von Felden J (15) Tal Grinspan L (16) Wang S (17) Kamphorst AO (18) Monga SP (19) Brown BD (20) Villanueva A (21) Llovet JM (22) Merad M (23) Lujambio A
PD-1 immune checkpoint inhibitors have produced encouraging results in hepatocellular carcinoma (HCC) patients. However, what determines resistance to anti-PD-1 therapies is unclear. We created a novel genetically-engineered mouse model of HCC that enables interrogating how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;p53-/- HCCs led to T cell-mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;p53-/- HCCs escaped the immune system by upregulating beta-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that beta-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, beta-catenin-driven tumors were resistant to anti-PD-1. In summary, beta-catenin activation promotes immune escape and resistance to anti-PD-1 and could represent a novel biomarker for HCC patient exclusion.
Author Info:
(1) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai. (2) Oncological Sciences, Icahn School of Medicine at Mount Sinai. (3) Icahn School of Medicine at
Mount Sinai. (4) Oncological Sciences, Icahn School of Medicine at Mount Sinai. (5) Mount Sinai School of Medicine. (6) Liver Diseases, Mt Sinai Liver Cancer program, MSSM. (7) Liver Diseases, Icahn School of Medicine at Mount Sinai. (8) Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai. (9) Icahn School of Medicine at Mount Sinai. (10) Icahn School of Medicine at Mount Sinai. (11) Liver Diseases, Mt Sinai Liver Cancer program, MSSM. (12) Pathology, University of Pittsburgh. (13) Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center. (14) Division of Liver Diseases, Icahn School of Medicine at Mount Sinai. (15) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai. (16) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai. (17) Oncological Sciences / Immunology Institute, Icahn School of Medicine at Mount Sinai. (18) Pathology and Medicine, University of Pittsburgh Medical Center. (19) Genetics and Genomic Sciences, Mount Sinai School of Medicine. (20) Division of Liver Disease, Mount Sinai School of Medicine. (21) Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai. (22) Department of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. (23) Oncological Sciences, Icahn School of Medicine at Mount Sinai amaia.lujambio@mssm.edu.
Citation: Cancer Discov 2019 Jun 11 Epub06/11/2019
