Uhl, Franziska M. and Chen, Sophia and O'Sullivan, David and Edwards-Hicks, Joy and Richter, Gesa and Haring, Eileen and Andrieux, Geoffroy and Halbach, Sebastian and Apostolova, Petya and Buscher, Jorg and Duquesne, Sandra and Melchinger, Wolfgang and Sauer, Barbara and Shoumariyeh, Khalid and Schmitt-Graeff, Annette and Kreutz, Marina and Lubbert, Michael and Duyster, Justus and Brummer, Tilman and Boerries, Melanie and Madl, Tobias and Blazar, Bruce R. and Gross, Olaf and Pearce, Erika L. and Zeiser, Robert (2020) Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans. SCIENCE TRANSLATIONAL MEDICINE, 12 (567): eabb8969. ISSN 1946-6234, 1946-6242
Full text not available from this repository. (Request a copy)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-gamma 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-y 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; HOST-DISEASE; RELAPSE; TRANSPLANTATION; SURVIVAL; INFUSIONS; THERAPY; IMPACT; PH; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Mar 2021 13:28 |
| Last Modified: | 08 Mar 2021 13:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43511 |
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