作者
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 Boerries,Tobias Madl,Bruce R. Blazar,Olaf Groß,Erika L. Pearce,Robert Zeiser
摘要
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.