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Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models

Ines Hammami, Jingkui Chen, Frederic Murschel, Vincenzo Bronte, Gregory De Crescenzo and Mario Jolicoeur

Article (2012)

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Abstract

Background: The tumor microenvironment contains a vast array of pro-and anti-inflammatory cytokines that alter myelopoiesis and lead to the maturation of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Incubating bone marrow (BM) precursors with a combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) generated a tumor-infiltrating MDSC-like population that impaired anti-tumor specific T-cell functions. This in vitro experimental approach was used to simulate MDSC maturation, and the cellular metabolic response was then monitored. A complementary experimental model that inhibited L-arginine (L-Arg) metabolizing enzymes in MSC-1 cells, an immortalized cell line derived from primary MDSCs, was used to study the metabolic events related to immunosuppression.Results: Exposure of BM cells to GM-CSF and IL-6 activated, within 24 h, L-Arg metabolizing enzymes which are responsible for the MDSCs immunosuppressive potential. This was accompanied by an increased uptake of L-glutamine (L-Gln) and glucose, the latter being metabolized by anaerobic glycolysis. The up-regulation of nutrient uptake lead to the accumulation of TCA cycle intermediates and lactate as well as the endogenous synthesis of L-Arg and the production of energy-rich nucleotides. Moreover, inhibition of L-Arg metabolism in MSC-1 cells down-regulated central carbon metabolism activity, including glycolysis, glutaminolysis and TCA cycle activity, and led to a deterioration of cell bioenergetic status. The simultaneous increase of cell specific concentrations of ATP and a decrease in ATP-to-ADP ratio in BM-derived MDSCs suggested cells were metabolically active during maturation. Moreover, AMP-activated protein kinase (AMPK) was activated during MDSC maturation in GM-CSF and IL-6-treated cultures, as revealed by the continuous increase of AMP-to-ATP ratios and the phosphorylation of AMPK. Likewise, AMPK activity was decreased in MSC-1 cells when L-Arg metabolizing enzymes were inhibited. Finally, inhibition of AMPK activity by the specific inhibitor Compound C (Comp-C) resulted in the inhibition of L-Arg metabolizing enzyme activity and abolished MDSCs immunosuppressive activity.Conclusions: We anticipate that the inhibition of AMPK and the control of metabolic fluxes may be considered as a novel therapeutic target for the recovery of the immunosurveillance process in cancer-bearing hosts.

Uncontrolled Keywords

AMP-Activated Protein Kinases; Adenosine Triphosphate; Arginine; Bone Marrow Cells; Cells, Cultured; Energy Metabolism; Glucose; Glutamine; Glycolysis; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppression; Interleukin-6; Myeloid Cells; Interleukin-6; Glutamine; Granulocyte-Macrophage Colony-Stimulating Factor; Adenosine Triphosphate; Arginine; AMP-Activated Protein Kinases; Glucose

Subjects: 1800 Chemical engineering > 1800 Chemical engineering
5100 Cell biology > 5100 Cell biology
9000 Health sciences > 9000 Health sciences
Department: Department of Chemical Engineering
Funders: CRSNG/NSERC, Canada Research Chair program, Québec-Italy Program of the Ministère du développement économique, innovation et exportation
Grant number: 216869-09, 208522, 226565, 06.2010
PolyPublie URL: https://publications.polymtl.ca/3413/
Journal Title: BMC Cell Biology (vol. 13, no. 1)
Publisher: BioMed Central
DOI: 10.1186/1471-2121-13-18
Official URL: https://doi.org/10.1186/1471-2121-13-18
Date Deposited: 07 Dec 2018 12:41
Last Modified: 05 Apr 2024 20:18
Cite in APA 7: Hammami, I., Chen, J., Murschel, F., Bronte, V., De Crescenzo, G., & Jolicoeur, M. (2012). Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models. BMC Cell Biology, 13(1). https://doi.org/10.1186/1471-2121-13-18

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