Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans

Franziska M. Uhl, Sophia Chen, David O'Sullivan, Joy Edwards-Hicks, Gesa Richter, Eileen Haring, Geoffroy Andrieux, Sebastian Halbach, Petya Apostolova, Jörg Büscher, Sandra Duquesne, Wolfgang Melchinger, Barbara Sauer, Khalid Shoumariyeh, Annette Schmitt-Graeff, Marina Kreutz, Michael Lübbert, Justus Duyster, Tilman Brummer, Melanie BoerriesTobias Madl, Bruce R. Blazar, Olaf Groß, Erika L. Pearce, Robert Zeiser

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis. We found that T cells of patients relapsing with AML after allo-HCT exhibited reduced glycolysis and interferon-γ production. Functional studies in multiple mouse models of leukemia showed that leukemia-derived lactic acid (LA) interfered with T cell glycolysis and proliferation. Mechanistically, LA reduced intracellular pH in T cells, led to lower transcription of glycolysis-related enzymes, and decreased activity of essential metabolic pathways. Metabolic reprogramming by sodium bicarbonate (NaBi) reversed the LA-induced low intracellular pH, restored metabolite concentrations, led to incorporation of LA into the tricarboxylic acid cycle as an additional energy source, and enhanced graft-versus-leukemia activity of murine and human T cells. NaBi treatment of post–allo-HCT patients with relapsed AML improved metabolic fitness and interferon-γ production in T cells. Overall, we show that metabolic reprogramming of donor T cells is a pharmacological strategy for patients with relapsed AML after allo-HCT.

Original languageEnglish (US)
Article numbereabb8969
JournalScience Translational Medicine
Volume12
Issue number567
DOIs
StatePublished - Oct 28 2020

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