LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid
Sonja-Maria Decking, Christina Bruß, Nathalie Babl, Sebastian Bittner, Sebastian Klobuch, Simone Thomas, Markus Feuerer, Petra Hoffmann, Katja Dettmer, Peter J. Oefner, Kathrin Renner, Marina Kreutz
Abstract
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.