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<sup>+</sup>...
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| Format: | Article |
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MDPI AG
2021-09-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/9/2334 |
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| author | Juan C. Garcia-Canaveras David Heo Sophie Trefely John Leferovich Chong Xu Benjamin I. Philipson Saba Ghassemi Michael C. Milone Edmund K. Moon Nathaniel W. Snyder Carl H. June Joshua D. Rabinowitz Roddy S. O’Connor |
| author_facet | Juan C. Garcia-Canaveras David Heo Sophie Trefely John Leferovich Chong Xu Benjamin I. Philipson Saba Ghassemi Michael C. Milone Edmund K. Moon Nathaniel W. Snyder Carl H. June Joshua D. Rabinowitz Roddy S. O’Connor |
| author_sort | Juan C. Garcia-Canaveras |
| collection | DOAJ |
| description | 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<sup>+</sup> by the enzyme <i>Lactobacillus brevis</i> NADH Oxidase (<i>LbNOX</i>), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if <i>LbNOX</i> promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing <i>LbNOX</i> have enhanced oxygen as well as lactate consumption and increased pyruvate production. <i>LbNOX</i> renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell’s expressing <i>LbNOX</i> 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 <i>LbNOX</i> is insufficient to promote tumor clearance. |
| first_indexed | 2024-03-10T07:49:14Z |
| format | Article |
| id | doaj.art-50d53015c0884756be813e46c6a7e1ed |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T07:49:14Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-50d53015c0884756be813e46c6a7e1ed2023-11-22T12:24:27ZengMDPI AGCells2073-44092021-09-01109233410.3390/cells10092334CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP ProductionJuan C. Garcia-Canaveras0David Heo1Sophie Trefely2John Leferovich3Chong Xu4Benjamin I. Philipson5Saba Ghassemi6Michael C. Milone7Edmund K. Moon8Nathaniel W. Snyder9Carl H. June10Joshua D. Rabinowitz11Roddy S. O’Connor12Department of Chemistry, Princeton University, Princeton, NJ 08544, USACenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USAA.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19140, USACenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USACenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USACenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USACenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USACenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19140, USAA.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19140, USACenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Chemistry, Princeton University, Princeton, NJ 08544, USACenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USAThe 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<sup>+</sup> by the enzyme <i>Lactobacillus brevis</i> NADH Oxidase (<i>LbNOX</i>), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if <i>LbNOX</i> promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing <i>LbNOX</i> have enhanced oxygen as well as lactate consumption and increased pyruvate production. <i>LbNOX</i> renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell’s expressing <i>LbNOX</i> 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 <i>LbNOX</i> is insufficient to promote tumor clearance.https://www.mdpi.com/2073-4409/10/9/2334armor CAR T-cells<i>Lactobacillus brevis</i> NADH oxidaseLDHA |
| spellingShingle | Juan C. Garcia-Canaveras David Heo Sophie Trefely John Leferovich Chong Xu Benjamin I. Philipson Saba Ghassemi Michael C. Milone Edmund K. Moon Nathaniel W. Snyder Carl H. June Joshua D. Rabinowitz Roddy S. O’Connor CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production Cells armor CAR T-cells <i>Lactobacillus brevis</i> NADH oxidase LDHA |
| title | CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production |
| title_full | CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production |
| title_fullStr | CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production |
| title_full_unstemmed | CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production |
| title_short | CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production |
| title_sort | car t cells depend on the coupling of nadh oxidation with atp production |
| topic | armor CAR T-cells <i>Lactobacillus brevis</i> NADH oxidase LDHA |
| url | https://www.mdpi.com/2073-4409/10/9/2334 |
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