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

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 VillanuevaJosep M. Llovet, Miriam Merad, Amaia Lujambio

Research output: Contribution to journalArticlepeer-review

236 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1124-1141
Number of pages18
JournalCancer Discovery
Volume9
Issue number8
DOIs
StatePublished - Aug 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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