American Association for Cancer Research
21598290cd190074-sup-215676_2_supp_5566746_pslt35.docx (395.69 kB)

Supplementary Data from β-Catenin Activation Promotes Immune Escape and Resistance to Anti–PD-1 Therapy in Hepatocellular Carcinoma

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journal contribution
posted on 2023-04-03, 22:41 authored by 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

Supplementary Data


Fundación Alfonso Martín Escudero Fellowship and the Damon Runyon-Rachleff Innovation

Damon Runyon-Rachleff Innovation


Department of Defense

Long-Term Human Frontiers Science Program

Belgian American Educational Foundation



Damon Runyon-Rachleff Innovation Award



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. 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

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