CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production.

TitleCAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production.
Publication TypeJournal Article
Year of Publication2021
AuthorsGarcía-Cañaveras, JC, Heo, D, Trefely, S, Leferovich, J, Xu, C, Philipson, BI, Ghassemi, S, Milone, MC, Moon, EK, Snyder, NW, June, CH, Rabinowitz, JD, O'Connor, RS
JournalCells
Volume10
Issue9
Date Published2021 09 06
ISSN2073-4409
KeywordsAdenosine Triphosphate, Adult, Animals, Female, Humans, Lactobacillus brevis, Male, Mice, Mice, Inbred NOD, Mice, SCID, Multienzyme Complexes, NAD, NADH, NADPH Oxidoreductases, Oxidation-Reduction, Receptors, Antigen, T-Cell, T-Lymphocytes
Abstract

<p>The metabolic milieu of solid tumors provides a barrier to chimeric antigen receptor (CAR) T-cell therapies. Excessive lactate or hypoxia suppresses T-cell growth, through mechanisms including NADH buildup and the depletion of oxidized metabolites. NADH is converted into NAD by the enzyme NADH Oxidase (), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing have enhanced oxygen as well as lactate consumption and increased pyruvate production. renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell's expressing showed no increased antitumor efficacy over control CAR T-cells. We hypothesize that T cells in hostile environments face dual metabolic stressors of excessive NADH and insufficient ATP production. Accordingly, futile T-cell NADH oxidation by is insufficient to promote tumor clearance.</p>

DOI10.3390/cells10092334
Alternate JournalCells
PubMed ID34571983
PubMed Central IDPMC8472053
Grant ListR01 CA226983 / CA / NCI NIH HHS / United States
587296 / / Saint Baldrick's Foundation /