IFNa Potentiates Anti-PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment
IFNa Potentiates Anti-PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment
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DOI：
10.1158/2159-8290.cd-21-1022
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发表时间：
2022-07-01
期刊：
影响因子：
28.2
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Hu, Bo;Yu, Mincheng;Fan, Jia
抗 PD-1 疗法在肝细胞癌 (HCC) 中的总体缓解率仍然较低。我们发现，联合使用 IFN α 和基于抗 PD-1 的免疫疗法可增强不可切除的 HCC 患者的抗肿瘤活性。在免疫功能正常的原位和自发性 HCC 模型中，IFN α 疗法与抗 PD-1 具有协同作用，并且联合治疗导致细胞毒性 CD27 + CD8 + T 细胞显着富集。从机制上讲，IFN α 通过抑制 HCC 细胞中的 FosB 转录来抑制 HIF1 α 信号传导，导致葡萄糖消耗能力降低，从而建立高葡萄糖微环境，通过浸润 CD8 + T 细胞中的 mTOR-FOXM1 信号传导促进 T 细胞共刺激分子 Cd27 的转录。总之，这些数据表明，IFN α 重新编程 HCC 肿瘤微环境中的葡萄糖代谢，从而释放 T 细胞的细胞毒能力并增强 PD-1 阻断诱导的免疫反应。我们的研究结果表明，IFN α 和抗 PD-1 联合治疗对于 HCC 患者来说是一种有效的新型联合策略。意义：我们的研究支持肿瘤葡萄糖代谢在 HCC 中 IFN α 介导的抗肿瘤免疫中的作用，肿瘤浸润 CD27 + CD8 + T 细胞可能是抗 PD-1 治疗患者分层的有前途的生物标志物。
The overall response rate for anti-PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of IFN alpha and anti-PD-1-based immu-notherapy resulted in enhanced antitumor activity in patients with unresectable HCC. In both immuno-competent orthotopic and spontaneous HCC models, IFN alpha therapy synergized with anti-PD-1 and the combination treatment led to signifi cant enrichment of cytotoxic CD27 +CD8+ T cells. Mechanistically, IFN alpha suppressed HIF1 alpha 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 IFN alpha reprograms glucose metabolism within the HCC tumor microenvironment, thereby liberating T-cell cytotoxic capacities and potentiating the PD-1 blockade-induced immune response. Our fi ndings suggest that IFN alpha 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 IFN alpha-mediated antitumor immunity in HCC, and tumor-infi ltrating CD27 +CD8+ T cells may be a promising biomarker for stratifying patients for anti-PD-1 therapy.