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

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 Lactoba...

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Detalles Bibliográficos
Autores principales: Garcia-Canaveras, Juan C., Heo, David, Trefely, Sophie, Leferovich, John, Xu, Chong, Philipson, Benjamin I., Ghassemi, Saba, Milone, Michael C., Moon, Edmund K., Snyder, Nathaniel W., June, Carl H., Rabinowitz, Joshua D., O’Connor, Roddy S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472053/
https://www.ncbi.nlm.nih.gov/pubmed/34571983
http://dx.doi.org/10.3390/cells10092334
Descripción
Sumario: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 Lactobacillus brevis NADH Oxidase (LbNOX), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if LbNOX promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing LbNOX have enhanced oxygen as well as lactate consumption and increased pyruvate production. LbNOX renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell’s expressing LbNOX 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 LbNOX is insufficient to promote tumor clearance.