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

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

doi:10.1126/scitranslmed.abb8969

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

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O'Sullivan, David
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Edwards-Hicks, Joy
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Apostalova, Petya
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Büscher, Jörg Martin
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pearce, Erika L.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://stm.sciencemag.org/content/12/567/eabb8969
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Citation

Uhl, F. M., Chen, S., O'Sullivan, D., Edwards-Hicks, J., Richter, G., Haring, E., et al. (2020). Metabolic reprogramming of donor T cells enhances graf-versus-leukemia effects in mice and humans. Science translational medicine: integrating medicine and science / American Association for the Advancement of Science, 12, eabb8969. doi:10.1126/scitranslmed.abb8969.

Cite as: https://hdl.handle.net/21.11116/0000-0007-E599-A

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.