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A dynamic metabolic flux analysis of myeloid-derived suppressor cells confirms immunosuppression-related metabolic plasticity

Guillaume Goffaux, Iness Hammami, Mario Jolicoeur

Article (2017)

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Recent years have witnessed an increasing interest at understanding the role of myeloid-derived suppressor cells (MDSCs) in cancer-induced immunosuppression, with efforts to inhibit their maturation and/or their activity. We have thus modelled MDSCs central carbon metabolism and bioenergetics dynamic, calibrating the model using experimental data on in vitro matured mice bone marrow cells into MDSCs. The model was then used to probe the cells metabolic state and dynamics, performing a dynamic metabolic flux analysis (dMFA) study. Indeed, MDSCs maturation correlates with a high glycolytic flux contributing to up to 95% of the global ATP turnover rate, while most of the glucose-derived carbon enters the TCA cycle. Model simulations also reveal that pentose phosphate pathway and oxidative phosphorylation activities were kept at minimal levels to ensure NADPH production and anabolic precursors synthesis. Surprisingly, MDSCs immunosuppressive activity, i.e. L-arginine uptake, metabolism and endogenous synthesis, only consumes sparse quantities of energy-rich nucleotides (ATP and NADPH). Therefore, model simulations suggest that MDSCs exhibit a heterogeous metabolic profile similar to tumour cells. This behavior is probably an indirect immunosuppressive mechanism where MDSCs reduce the availability of carbon sources in the tumour periphery microenvironment, which could explain the dysfuntion and death of immune effector cells.

Uncontrolled Keywords

Animals; *Energy Metabolism; *Immunomodulation; Metabolic Flux Analysis; Metabolic Networks and Pathways; Metabolome; Metabolomics/methods; Mice; Myeloid-Derived Suppressor Cells/*immunology/*metabolism

Subjects: 1800 Chemical engineering > 1802 Biochemical engineering
1900 Biomedical engineering > 1900 Biomedical engineering
Department: Department of Chemical Engineering
Grant number: 093865
PolyPublie URL: https://publications.polymtl.ca/4897/
Journal Title: Scientific Reports (vol. 7)
Publisher: Nature
DOI: 10.1038/s41598-017-10464-1
Official URL: https://doi.org/10.1038/s41598-017-10464-1
Date Deposited: 17 Dec 2021 11:14
Last Modified: 10 Nov 2022 10:48
Cite in APA 7: Goffaux, G., Hammami, I., & Jolicoeur, M. (2017). A dynamic metabolic flux analysis of myeloid-derived suppressor cells confirms immunosuppression-related metabolic plasticity. Scientific Reports, 7, 9850 (14 pages). https://doi.org/10.1038/s41598-017-10464-1


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