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Decking, Sonja-Maria; Bruss, Christina; Babl, Nathalie; Bittner, Sebastian; Klobuch, Sebastian; Thomas, Simone; Feuerer, Markus; Hoffmann, Petra; Dettmer, Katja; Oefner, Peter J; Renner, Kathrin; Kreutz, Marina
International journal of molecular sciences, 05/2022, Volume: 23, Issue: 11Journal Article
Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy.
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