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

Publication ,  Journal Article
Siska, PJ; van der Windt, GJW; Kishton, RJ; Cohen, S; Eisner, W; MacIver, NJ; Kater, AP; Weinberg, JB; Rathmell, JC
Published in: J Immunol
September 15, 2016

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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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

September 15, 2016

Volume

197

Issue

6

Start / End Page

2532 / 2540

Location

United States

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • T-Lymphocytes
  • Spleen
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Multiprotein Complexes
  • Mice
  • Mechanistic Target of Rapamycin Complex 1
  • Lymphocyte Activation
  • Leukemia, Lymphocytic, Chronic, B-Cell
 

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Siska, P. J., van der Windt, G. J. W., Kishton, R. J., Cohen, S., Eisner, W., MacIver, N. J., … Rathmell, J. C. (2016). Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia. J Immunol, 197(6), 2532–2540. https://doi.org/10.4049/jimmunol.1502464
Siska, Peter J., Gerritje J. W. van der Windt, Rigel J. Kishton, Sivan Cohen, William Eisner, Nancie J. MacIver, Arnon P. Kater, J Brice Weinberg, and Jeffrey C. Rathmell. “Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.J Immunol 197, no. 6 (September 15, 2016): 2532–40. https://doi.org/10.4049/jimmunol.1502464.
Siska PJ, van der Windt GJW, Kishton RJ, Cohen S, Eisner W, MacIver NJ, et al. Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia. J Immunol. 2016 Sep 15;197(6):2532–40.
Siska, Peter J., et al. “Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.J Immunol, vol. 197, no. 6, Sept. 2016, pp. 2532–40. Pubmed, doi:10.4049/jimmunol.1502464.
Siska PJ, van der Windt GJW, Kishton RJ, Cohen S, Eisner W, MacIver NJ, Kater AP, Weinberg JB, Rathmell JC. Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia. J Immunol. 2016 Sep 15;197(6):2532–2540.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

September 15, 2016

Volume

197

Issue

6

Start / End Page

2532 / 2540

Location

United States

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • T-Lymphocytes
  • Spleen
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Multiprotein Complexes
  • Mice
  • Mechanistic Target of Rapamycin Complex 1
  • Lymphocyte Activation
  • Leukemia, Lymphocytic, Chronic, B-Cell