β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma

By M. Ruiz de Galarreta, Erin R. Bresnahan, Pedro Molina-Sánchez, K. Lindblad, B. Maier, D. Sia, M. Puigvehí, Verónica Miguela, M. Casanova-Acebes, Maxime Dhainaut and 13 more. Cancer Discovery, 2019

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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 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.

Subfields: Molecular Biology, Oncology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/268d199569e4fe6828bb680a84a2a4feb7d615f3

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