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NAD + supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells.
- Source :
-
Cell reports [Cell Rep] 2021 Aug 10; Vol. 36 (6), pp. 109516. - Publication Year :
- 2021
-
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 <superscript>+</superscript> , 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 <superscript>+</superscript> 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 <superscript>+</superscript> supplementation enhanced the tumor-killing efficacy of T cells. Collectively, this study reveals that an impaired TCR-TUB-NAMPT-NAD <superscript>+</superscript> axis leads to T cell dysfunction in the tumor microenvironment, and an over-the-counter nutrient supplement of NAD <superscript>+</superscript> could boost T-cell-based immunotherapy.<br />Competing Interests: Declaration of interests Authors declare no competing interests.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 36
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 34380043
- Full Text :
- https://doi.org/10.1016/j.celrep.2021.109516