1. NAD + supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells.
- Author
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Wang Y, Wang F, Wang L, Qiu S, Yao Y, Yan C, Xiong X, Chen X, Ji Q, Cao J, Gao G, Li D, Zhang L, Guo Z, Wang R, Wang H, and Fan G
- Subjects
- Adoptive Transfer, Animals, Cell Death drug effects, Cell Line, Tumor, Energy Metabolism drug effects, Humans, Lymphocyte Activation drug effects, Lymphocytes, Tumor-Infiltrating drug effects, Mice, Inbred NOD, Neoplasms genetics, Nicotinamide Phosphoribosyltransferase metabolism, T-Lymphocytes drug effects, Mice, Adaptor Proteins, Signal Transducing metabolism, Lymphocytes, Tumor-Infiltrating immunology, NAD pharmacology, Neoplasms immunology, Neoplasms pathology, Nicotinamide Phosphoribosyltransferase genetics, T-Lymphocytes immunology, Transcription, Genetic drug effects
- 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., Competing Interests: Declaration of interests Authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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