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

被引：83

作者：

Uhl, Franziska M. ^{[1
,2
]}

Chen, Sophia ^{[1
,3
]}

O'Sullivan, David ^{[4
]}

Edwards-Hicks, Joy ^{[4
]}

Richter, Gesa ^{[5
]}

Haring, Eileen ^{[1
,2
]}

Andrieux, Geoffroy ^{[6
,7
,8
]}

Halbach, Sebastian ^{[9
]}

Apostolova, Petya ^{[1
,4
]}

Buscher, Jorg ^{[4
]}

Duquesne, Sandra ^{[1
]}

Melchinger, Wolfgang ^{[1
]}

Sauer, Barbara ^{[1
]}

Shoumariyeh, Khalid ^{[1
]}

Schmitt-Graeff, Annette ^{[10
]}

Kreutz, Marina ^{[11
,12
]}

Lubbert, Michael ^{[1
]}

Duyster, Justus ^{[1
]}

Brummer, Tilman ^{[7
,8
,9
]}

Boerries, Melanie ^{[6
,7
,8
]}

Madl, Tobias ^{[5
,13
]}

Blazar, Bruce R. ^{[14
]}

Gross, Olaf ^{[15
,16
,17
]}

Pearce, Erika L. ^{[4
]}

Zeiser, Robert ^{[1
,16
,17
]}

机构：

[1] Univ Freiburg, Fac Med, Med Ctr, Dept Internal Med 1, D-79106 Freiburg, Germany

[2] Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany

[3] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Immunol, New York, NY 10065 USA

[4] Max Planck Inst Immunobiol & Epigenet, Dept Immunometab, D-79108 Freiburg, Germany

[5] Med Univ Graz, Gottfried Schatz Res Ctr Cell Signaling Metab & A, Mol Biol & Biochem, A-8010 Graz, Austria

[6] Univ Freiburg, Fac Med, Med Ctr, Inst Med Bioinformat & Syst Med, D-79110 Freiburg, Germany

[7] German Canc Consortium DKTK, Partner Site Freiburg, D-69120 Heidelberg, Germany

[8] German Canc Res Ctr, D-69120 Heidelberg, Germany

[9] Univ Freiburg, Fac Med, Inst Mol Med & Cell Res IMMZ, D-79104 Freiburg, Germany

[10] Univ Freiburg, D-79085 Freiburg, Germany

[11] Univ Hosp Regensburg, Internal Med 3, D-93042 Regensburg, Germany

[12] Regensburg Ctr Intervent Immunol RCI, D-93053 Regensburg, Germany

[13] BioTechMed Graz, A-8010 Graz, Austria

[14] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA

[15] Univ Freiburg, Fac Med, Med Ctr, Inst Neuropathol, D-79106 Freiburg, Germany

[16] Univ Freiburg, Signalling Res Ctr BIOSS, D-79106 Freiburg, Germany

[17] Univ Freiburg, CIBSS Ctr Integrat Biol Signalling Studies, D-79106 Freiburg, Germany

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2020年 / 12卷 / 567期

基金：

欧洲研究理事会;

关键词：

ACUTE MYELOID-LEUKEMIA; HOST-DISEASE; RELAPSE; TRANSPLANTATION; SURVIVAL; INFUSIONS; THERAPY; IMPACT; PH;

D O I：

10.1126/scitranslmed.abb8969

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

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-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.

引用

页数：14

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