NAD(+) supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells
NAD(+) supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells
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NAD( ) 补充剂通过挽救肿瘤浸润 T 细胞中 TUB 介导的 NAMPT 转录缺陷来增强肿瘤杀伤功能
DOI：
10.1016/j.celrep.2021.109516
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发表时间：
2021
期刊：
影响因子：
8.8
通讯作者：
Fan Gaofeng（最后通讯）
中科院分区：
文献类型：
--
作者：
Wang Yuetong;Wang Fei;Wang Lihua;Qiu Shizhen;Yao Yufeng;Yan Chenxu;Xiong Xuexue;Chen Xuyong;Ji Quanquan;Cao Jian;Gao Ganglong;Li Dake;Zhang Liye;Guo Zhiqian;Wang Ruoning;Wang Haopeng;Fan Gaofeng（最后通讯）
尽管肿瘤浸润淋巴细胞（til）保持其增殖、持续和根除肿瘤的能力，但它们经常在原位功能失调。通过进行全基因组CRISPR和代谢抑制剂筛选，我们发现烟酰胺磷酸核糖基转移酶（NAMPT）是T细胞激活所必需的。NAMPT在TILs中含量较低，其表达受转录因子Tubby （TUB）控制，其活性依赖于T细胞受体-磷脂酶Cγ (TCR-PLCγ)信号轴。NAD+的合成依赖于nampt介导的挽救途径，其细胞内水平在TILs中也降低。液相色谱-质谱（LC-MS）和同位素标记研究证实，NAD+耗竭导致糖酵解抑制，线粒体功能中断，并抑制ATP合成。令人兴奋的是，过继性CAR-T和抗pd1免疫检查点阻断小鼠模型都表明，补充NAD+增强了T细胞的肿瘤杀伤效果。总的来说，本研究揭示了TCR-TUB-NAMPT-NAD+轴受损导致肿瘤微环境中的T细胞功能障碍，NAD+的非处方营养补充剂可以促进T细胞免疫治疗。
Although tumor-infiltrating lymphocytes (TILs) maintain their ability to proliferate, persist, and eradicate tumors, they are frequently dysfunctionalin situ. By performing both whole-genome CRISPR and metabolic inhibitor screens, we identify that nicotinamide phosphoribosyltransferase (NAMPT) is required for T cell activation. NAMPT is low in TILs, and its expression is controlled by the transcriptional factor Tubby (TUB), whose activity depends on the T cell receptor-phospholipase C gamma (TCR-PLCγ) signaling axis. The intracellular level of NAD+, whose synthesis is dependent on the NAMPT-mediated salvage pathway, is also decreased in TILs. Liquid chromatography-mass spectrometry (LC-MS) and isotopic labeling studies confirm that NAD+depletion led to suppressed glycolysis, disrupted mitochondrial function, and dampened ATP synthesis. Excitingly, both adoptive CAR-T and anti-PD1 immune checkpoint blockade mouse models demonstrate that NAD+supplementation enhanced the tumor-killing efficacy of T cells. Collectively, this study reveals that an impaired TCR-TUB-NAMPT-NAD+axis leads to T cell dysfunction in the tumor microenvironment, and an over-the-counter nutrient supplement of NAD+could boost T-cell-based immunotherapy.