IFNα Potentiates Anti–PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment
Bo Hu, Mincheng Yu, Xiaolu Ma, Jialei Sun, Chenglong Liu, Chunyan Wang, Suiyi Wu, Pei‐Yao Fu, Zhen Yang, Yungang He, Yuanyuan Zhu, Cheng Huang, Xin‐Rong Yang, Ying–Hong Shi, Shuang‐Jian Qiu, Hui‐Chuan Sun, Andrew X. Zhu, Jian Zhou, Yang Xu, Di Zhu, Jia Fan
Abstract
The overall response rate for anti-PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of IFNα and anti-PD-1-based immunotherapy resulted in enhanced antitumor activity in patients with unresectable HCC. In both immunocompetent orthotopic and spontaneous HCC models, IFNα therapy synergized with anti-PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+CD8+ T cells. Mechanistically, IFNα suppressed HIF1α signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing a high-glucose microenvironment that fostered transcription of the T-cell costimulatory molecule Cd27 via mTOR-FOXM1 signaling in infiltrating CD8+ T cells. Together, these data reveal that IFNα reprograms glucose metabolism within the HCC tumor microenvironment, thereby liberating T-cell cytotoxic capacities and potentiating the PD-1 blockade-induced immune response. Our findings suggest that IFNα and anti-PD-1 cotreatment is an effective novel combination strategy for patients with HCC. SIGNIFICANCE: Our study supports a role of tumor glucose metabolism in IFNα-mediated antitumor immunity in HCC, and tumor-infiltrating CD27+CD8+ T cells may be a promising biomarker for stratifying patients for anti-PD-1 therapy. See related commentary by Kao et al., p. 1615. This article is highlighted in the In This Issue feature, p. 1599.