文献类型：期刊文献

英文题名：NAD+ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells

作者：Wang, Yuetong[1];Wang, Fei[1];Wang, Lihua[2];Qiu, Shizhen[1];Yao, Yufeng[1];Yan, Chenxu[3];Xiong, Xuexue[1];Chen, Xuyong[4];Ji, Quanquan[5];Cao, Jian[6];Gao, Ganglong[7];Li, Dake[6];Zhang, Liye[1];Guo, Zhiqian[3];Wang, Ruoning[4];Wang, Haopeng[1];Fan, Gaofeng[1]

机构：[1]ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China;[2]Shanghai Jiao Tong Univ, Int Peace Matern & Child Hlth Hosp, Sch Med, Dept Gynecol, Shanghai, Peoples R China;[3]East China Univ Sci & Technol, Sch Chem & Mol Engn, Inst Fine Chem, Shanghai Key Lab Funct Mat Chem, Shanghai, Peoples R China;[4]Ohio State Univ, Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Dis, Res Inst,Hematol Oncol & BMT, Columbus, OH 43210 USA;[5]Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Cell Biol, Shanghai, Peoples R China;[6]Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Dept Gynecol, Womens Hosp, Nanjing, Peoples R China;[7]Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Shanghai, Peoples R China

年份：2021

卷号：36

期号：6

外文期刊名：CELL REPORTS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000684598900015)】；

基金：The authors thank the staff members of the Animal Facility at the National Facility for Protein Science in Shanghai (NFPS), Zhangjiang Lab, China, for providing the support in mouse housing and care. The authors thank the staff members of the Multi-Omics Facility of Shanghaitech University for technical supports with the LC-MS/MS experiment. The authors thank Prof. Tiffany Horng for their critical reading and suggestions. The authors also thank Shengmiao Chen, Jiali Zhang, and Wentao Li for their technical supports. This work was supported by the Ministry of Science and Technology of China (2018YFC1004603 to G.F.), the National Natural Science Foundation of China (31872831 and 32070776 to G.F., 31670919 to H.W.), the Shanghai Science and Technology Commission (19JC1413800 to G.F.), the Shanghai Shuguang program (19SG55 to G.F.), the Shanghai Sailing Program (21YF1429900 to Y.W.), and a ShanghaiTech University startup grant.

语种：英文

摘要：Although tumor-infiltrating lymphocytes (TILs) maintain their ability to proliferate, persist, and eradicate tumors, they are frequently dysfunctional in 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-PLC gamma) 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.