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

Franziska M. 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-Graeff, Marina Kreutz, Michael Lübbert, Justus Duyster, Tilman Brummer, Melanie BoerriesTobias Madl, Bruce R. Blazar, Olaf Groß, Erika L. Pearce, Robert Zeiser

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article numbereabb8969
JournalScience Translational Medicine
Volume12
Issue number567
DOIs
StatePublished - Oct 28 2020

Bibliographical note

Funding Information:
We thank the central diagnostics facility of the Medical Center?University of Freiburg for the blood gas analysis of patient blood. We thank M. R?ssler for helping design the illustration in fig. S19. We are thankful to the animal caretakers at Medical Center?University of Freiburg for excellent support. Funding: This study was supported by the DFG under Germany?s Excellence Strategy?EXC 2189 Project ID: 390939984 to R.Z., DFG individual grant 872/4-1 to R.Z., SFB1160 TP B09 to R.Z., and TP Z02 to M.B., the European Union: GVHDCure Proposal no. 681012 ERC consolidator grant to R.Z., the Deutsche Krebshilfe (grant number 70113473), the Jose Carreras Leukemia foundation (grant number DJCLS 01R/2019) to R.Z., the Max Planck Society and National Cancer Institute (grant R01CA18112) to E.L.P., SFB221 TP B12 to M.K., R01HL56067 and R3734495 to B.R.B., NHLBI R01 HL11879 and NIAID R37 AI34495 to B.R.B., German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept CoNfirm (FKZ 01ZX1708F) and MIRACUM within the Medical Informatics Funding Scheme (FKZ 01ZZ1801B) to M.B., Austrian Research Foundation grants P28854, I3792, and DK-MCD W1226, Austrian Research Promotion Agency (FFG) grants 864690 and 870454, the Integrative Metabolism Research Center Graz, Austrian Infrastructure Program 2016/2017, the Styrian Government (Zukunftsfonds), and BioTechMed-Graz (flagship project) to T.M., the DFG through SFB 1160, SFB/TRR 167, SFB 1425, GRK 2606 to O.G., and (under the Excellence Strategy of the German Federal and State Governments) through CIBSS - EXC-2189 - Project ID 390939984 to O.G. as well as by the European Research Council (ERC)

Publisher Copyright:
Copyright © 2020 The Authors,

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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