Funding
Fundación Alfonso Martín Escudero Fellowship and the Damon Runyon-Rachleff Innovation
Damon Runyon-Rachleff Innovation
NIH/NIAID
Department of Defense
Long-Term Human Frontiers Science Program
Belgian American Educational Foundation
DoD
NCI
Damon Runyon-Rachleff Innovation Award
ARTICLE 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.
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
