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

Uhl FM, Chen S, O'Sullivan D, Edwards-Hicks J, Richter G, Haring E, Andrieux G, Halbach S, Apostolova P, Buscher J, Duquesne S, Melchinger W, Sauer B, Shoumariyeh K, Schmitt-Graeff A, Kreutz M, Lubbert M, Duyster J, Brummer T, Boerries M, Madl T, Blazar BR, Gross O, Pearce EL, Zeiser R (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 12

Article Number: eabb8969

Journal Issue: 567

DOI: 10.1126/scitranslmed.abb8969

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.

Involved external institutions

Albert-Ludwigs-Universität Freiburg DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE) Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics DE Germany (DE) University of Minnesota (UMN) US United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Uhl, F.M., Chen, S., O'Sullivan, D., Edwards-Hicks, J., Richter, G., Haring, E.,... Zeiser, R. (2020). Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans. Science Translational Medicine, 12(567). https://doi.org/10.1126/scitranslmed.abb8969

MLA:

Uhl, Franziska M., et al. "Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans." Science Translational Medicine 12.567 (2020).

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