Research ArticleCancer

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

See allHide authors and affiliations

Science Translational Medicine  28 Oct 2020:
Vol. 12, Issue 567, eabb8969
DOI: 10.1126/scitranslmed.abb8969

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

A basic treatment for leukemia

For patients with acute myeloid leukemia, hematopoietic stem cell transplant offers a chance of curing the underlying cancer, in part because of the graft-versus-leukemia effect, or anticancer activity of transplanted T cells. Unfortunately, this does not always work, and engrafted T cells often fail to control the leukemia. By studying patients with acute myeloid leukemia who relapsed after hematopoietic stem cell transplant, Uhl et al. found that lactic acid produced by leukemic cells specifically interfered with T cell activity. The detrimental effects of lactic acid could be overcome with sodium bicarbonate, which improved T cell metabolic fitness in both mouse models and human patients.

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.

View Full Text

Stay Connected to Science Translational Medicine