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

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

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Metabolic 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 SchmittGraeff,

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) - reprogramming , leukemia , cancer research , biology , microbiology and biotechnology , chemistry , immunology , genetics , cell

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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