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Journal article
CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production
Cells (Basel, Switzerland), v 10(9), p2334
01 Sep 2021
PMID: 34571983
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production
- Creators
- Juan C. Garcia-Canaveras - Princeton UniversityDavid Heo - University of PennsylvaniaSophie Trefely - Drexel UniversityJohn Leferovich - University of PennsylvaniaChong Xu - University of PennsylvaniaBenjamin Philipson - University of PennsylvaniaSaba Ghassemi - University of PennsylvaniaMichael C. Milone - University of PennsylvaniaEdmund K. Moon - University of PennsylvaniaNathaniel W. Snyder - Drexel UniversityCarl H. June - University of PennsylvaniaJoshua D. Rabinowitz - ChemistryRoddy S. O'Connor - Univ Penn, Perelman Sch Med, Ctr Cellular Immunotherapies, Philadelphia, PA 19104 USA
- Publication Details
- Cells (Basel, Switzerland), v 10(9), p2334
- Publisher
- Mdpi
- Number of pages
- 16
- Grant note
- National Blood Foundation (NBF) Early Career Scientific Research Grant 587296 / St. Baldrick's Foundation Scholar Award RO1CA226983-04 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000699190100001
- Scopus ID
- 2-s2.0-85115891977
- Other Identifier
- 991019167958104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology