肿瘤微环境
CD8型
细胞毒性T细胞
癌症研究
T细胞
癌症免疫疗法
免疫疗法
免疫系统
化学
生物
CD19
细胞生物学
体外
免疫学
生物化学
肿瘤细胞
作者
Jie Cheng,Jinxin Yan,Ying Liu,Jiangzhou Shi,Haoyu Wang,H. Pang M. Zhou,Ying‐Lin Zhou,Tongcun Zhang,Lina Zhao,Xianbin Meng,H. Gong,Xin‐Xiang Zhang,Haichuan Zhu,Peng Jiang
出处
期刊:Cell Metabolism
[Elsevier]
日期:2023-05-12
卷期号:35 (6): 961-978.e10
被引量:47
标识
DOI:10.1016/j.cmet.2023.04.017
摘要
Summary
Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
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