TY - JOUR
T1 - Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans
AU - Uhl, Franziska M.
AU - Chen, Sophia
AU - O'Sullivan, David
AU - Edwards-Hicks, Joy
AU - Richter, Gesa
AU - Haring, Eileen
AU - Andrieux, Geoffroy
AU - Halbach, Sebastian
AU - Apostolova, Petya
AU - Büscher, Jörg
AU - Duquesne, Sandra
AU - Melchinger, Wolfgang
AU - Sauer, Barbara
AU - Shoumariyeh, Khalid
AU - Schmitt-Graeff, Annette
AU - Kreutz, Marina
AU - Lübbert, Michael
AU - Duyster, Justus
AU - Brummer, Tilman
AU - Boerries, Melanie
AU - Madl, Tobias
AU - Blazar, Bruce R.
AU - Groß, Olaf
AU - Pearce, Erika L.
AU - Zeiser, Robert
N1 - Publisher Copyright:
Copyright © 2020 The Authors,
PY - 2020/10/28
Y1 - 2020/10/28
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.abb8969
DO - 10.1126/scitranslmed.abb8969
M3 - Article
C2 - 33115954
AN - SCOPUS:85094812706
SN - 1946-6234
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 567
M1 - eabb8969
ER -