Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia

Journal of Immunology - Tập 197 Số 6 - Trang 2532-2540 - 2016
Peter J. Siska1,2,3, Gerritje J. W. van der Windt4, Rigel J. Kishton1, Sivan Cohen1, William Eisner5, Nancie J. MacIver5, Arnon P. Kater6,7, J. Brice Weinberg8,9, Jeffrey C. Rathmell1,2,3
1*Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;
2†Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232;
3‡Department of Cancer Biology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232;
4§Department of Experimental Immunology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands;
5¶Department of Pediatrics, Duke University, Durham, NC 27710;
6#Lymphoma and Myeloma Center Amsterdam, 1105 AZ Amsterdam, the Netherlands;
7‖Department of Hematology, Academic Medical Center, 1100 DD Amsterdam, the Netherlands;
8**Department of Medicine, Duke University, Durham, NC 27708; and
9††Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC 27705

Tóm tắt

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.

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Journal of Immunology

Tập 197 Số 6

2532-2540

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