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

TLDR

PD‑1 checkpoint inhibitors show promise in hepatocellular carcinoma, yet the factors driving resistance remain poorly understood. The authors developed a genetically engineered mouse model of HCC to investigate how specific genetic alterations influence immune surveillance and response to immunotherapy. The model combines MYC overexpression with Trp53 loss and, in some cohorts, CTNNB1 activation to assess tumor–immune interactions. Antigen expression in MYC;Trp53‑/‑ tumors elicited T‑cell surveillance and improved survival, but CTNNB1 activation enabled immune escape by impairing dendritic recruitment and T‑cell activity; restoring CCL5 rescued surveillance, and CTNNB1‑driven tumors were resistant to anti‑PD‑1, indicating β‑catenin as a biomarker for exclusion. The article is highlighted in the issue and includes commentary by Berraondo et al.

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.