Car t-cells depend on the coupling of nadh oxidation with atp production

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number2334
JournalCells
Volume10
Issue number9
DOIs
StatePublished - Sep 2021

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Keywords

  • Armor CAR T-cells
  • Lactobacillus brevis NADH oxidase
  • LDHA

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