癌症研究
肿瘤微环境
细胞毒性T细胞
免疫疗法
免疫系统
CD8型
肝细胞癌
PD-L1
生物
医学
化学
免疫学
生物化学
体外
作者
Bo Hu,Mincheng Yu,Xiao-Lu Ma,Jia‐Lei 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
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2022-04-12
卷期号:12 (7): 1718-1741
被引量:91
标识
DOI:10.1158/2159-8290.cd-21-1022
摘要
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
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