title: Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.
abstract: Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction.
authors: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232;
authors: Peter J
authors: 0000-0002-1521-6213
authors: PJ
authors: Siska
authors: Department of Experimental Immunology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands;
authors: Gerritje J W
authors: GJ
authors: van der Windt
authors: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;
authors: Rigel J
authors: 0000-0002-5682-3896
authors: RJ
authors: Kishton
authors: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;
authors: Sivan
authors: S
authors: Cohen
authors: Department of Pediatrics, Duke University, Durham, NC 27710;
authors: William
authors: W
authors: Eisner
authors: Department of Pediatrics, Duke University, Durham, NC 27710;
authors: Nancie J
authors: 0000-0003-3676-9391
authors: NJ
authors: MacIver
authors: Department of Hematology, Academic Medical Center, 1100 DD Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors: Arnon P
authors: 0000-0003-3190-1891
authors: AP
authors: Kater
authors: Department of Medicine, Duke University, Durham, NC 27708; and Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC 27705.
authors: J Brice
authors: 0000-0003-4052-5576
authors: JB
authors: Weinberg
authors: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232; jeff.rathmell@vanderbilt.edu.
authors: Jeffrey C
authors: JC
authors: Rathmell
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D045744:Cell Line, Tumor; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D006019:Glycolysis; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D008213:Lymphocyte Activation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose