A Dynamic Metabolic Flux Analysis of Myeloid-Derived Suppressor Cells Confirms Immunosuppression-Related Metabolic Plasticity

Abstract

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.

Energy metabolism manipulates the fate and function of tumour myeloid-derived suppressor cells

“…50 Dynamic metabolic flux analysis, a unique tool that can quantify extracellular and intracellular nutrient and metabolite concentrations, demonstrated that MDSCs exhibit the Warburg effect during their maturation with high glucose and glutamine uptake rates, a reduced oxygen consumption rate (OCR) and that approximately 95% of the ATP generated was obtained through a glycolysis-dependent mechanism. 51 Tumourderived MDSCs exhibit high glycolysis upregulation, and its metabolite phosphoenolpyruvate could protect MDSCs from apoptosis and contribute to their survival. 38 Owing to the high glucose uptake rates of both tumour cells and MDSCs, immune cells do not have any metabolic elasticity to acclimate to the condition of low oxygen tension and limited glucose availability, which could result in immune cell dysfunction and death, indirectly facilitating tumour escape and progression.…”

The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates

“…A dynamic metabolic flux analysis revealed that a high glycolytic flux is needed for the maturation of MDSCs from bone marrow precursors and suggested an indirect mechanism by which the consumption of carbon sources by MDSCs results in the suppression of effector T cells. 48 Previous results showed that glycolysis promotes MDSC survival in tumorbearing animals by preventing ROS-mediated apoptosis via the antioxidant activity of the glycolytic intermediate phosphoenolpyruvate. 49 Conversely, SIRT1 reprogrammed MDSCs into inflammatory M1 macrophages by shifting them to HIF-1α-dependent glycolysis.…”

Metabolic therapies inhibit tumor growth in vivo and in silico

“…The metabolic network presented here and displayed in Fig. 3 has been modified from previous models of Chinese Hamster Ovary cells (CHO) and mouse myeloid derived suppressor cells (MD-SCs) 34,36–39 . It includes 35 enzymatic reactions describing the fate of 52 metabolites.…”