1. Academic Validation
  2. 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.
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.

Figures
Products