Data from β-Catenin Activation Promotes Immune Escape and Resistance to Anti–PD-1 Therapy in Hepatocellular Carcinoma
Year: 2023
Type: other
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 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
Authors: Marina Ruiz de Galarreta, Erin Bresnahan, Pedro Molina-Sánchez, Katherine E. Lindblad, Barbara Maier, Daniela Sia, Marc Puigvehi, Verónica Miguela, María Casanova-Acebes, Maxime Dhainaut, Carlos Villacorta-Martin, Aatur D. Singhi, Akshata Moghe, Johann von Felden, Lauren Tal Grinspan, Shuang Wang, Alice O. Kamphorst, Satdarshan P. Monga, Brian D. Brown, Augusto Villanueva, Josep M. Llovet, Miriam Merad, Amaia Lujambio
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4392691576