2. Academic Validation
  3. 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

  • Cell Rep. 2021 Aug 10;36(6):109516. doi: 10.1016/j.celrep.2021.109516.
Yuetong Wang 1,  Fei Wang 1,  Lihua Wang 2,  Shizhen Qiu 1,  Yufeng Yao 1,  Chenxu Yan 3,  Xuexue Xiong 1,  Xuyong Chen 4,  Quanquan Ji 5,  Jian Cao 6,  Ganglong Gao 7,  Dake Li 6,  Liye Zhang 1,  Zhiqian Guo 3,  Ruoning Wang 4,  Haopeng Wang 8,  Gaofeng Fan 9
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 2 Department of Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Shanghai Key Laboratory of Functional Materials Chemistry, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China.
  • 4 Center for Childhood Cancer and Blood Diseases, Hematology/Oncology & BMT, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH, USA.
  • 5 State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 6 Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.
  • 7 Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • 8 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: wanghp@shanghaitech.edu.cn.
  • 9 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: fangf@shanghaitech.edu.cn.
PMID: 34380043 DOI: 10.1016/j.celrep.2021.109516
Abstract

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-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.

Keywords

CAR-T; NAD(+) supplement; NAMPT; PD-1; T cell activation; TUB; cancer immunotherapy.

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