Format

Send to

Choose Destination
J Immunol. 2016 Sep 15;197(6):2532-40. doi: 10.4049/jimmunol.1502464. Epub 2016 Aug 10.

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

Author information

1
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;
2
Department of Experimental Immunology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands;
3
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;
4
Department of Pediatrics, Duke University, Durham, NC 27710;
5
Department of Hematology, Academic Medical Center, 1100 DD Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam, 1105 AZ Amsterdam, the Netherlands;
6
Department of Medicine, Duke University, Durham, NC 27708; and Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC 27705.
7
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.

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.

PMID:
27511728
PMCID:
PMC5010978
DOI:
10.4049/jimmunol.1502464
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center