免疫系统
生物
癌细胞
细胞毒性T细胞
癌症研究
癌症免疫疗法
细胞溶解
癌变
免疫疗法
T细胞
细胞生物学
癌症
免疫学
生物化学
体外
遗传学
作者
Zheng Liu,Wenjie Liu,Wei Wang,Yibao Ma,Yufeng Wang,David L. Drum,Jinyang Cai,Hallie Blevins,Eun Lee,Syed Hasnain Ali Shah,Paul B. Fisher,Xinhui Wang,Xianjun Fang,Chunqing Guo,Xiang-Yang Wang
标识
DOI:10.1073/pnas.2302878120
摘要
Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell–derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.
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