Open AccessMetabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans
Author(s) -
Franziska Maria 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-Gräeff,
Marina Kreutz,
Michael Lübbert,
Justus Duyster,
Tilman Brummer,
Melanie Boerries,
Tobias Madl,
Bruce R. Blazar,
Olaf Groß,
Erika L. Pearce,
Robert Zeiser
Publication year - 2020
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.abb8969
Subject(s) - leukemia , glycolysis , anaerobic glycolysis , cancer research , myeloid leukemia , haematopoiesis , citric acid cycle , transplantation , chemistry , biology , stem cell , biochemistry , immunology , metabolism , medicine , microbiology and biotechnology
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.