Table 1 Regulation of MDSC expansion and suppressive mechanisms

Mobilization and expansion

Granulocyte/macrophage colony-stimulating factor (GM-CSF), macrophage CSF (M-CSF), granulocyte CSF (G-CSF), IL-6, IL-1β, beta-fibroblast growth factor (β-FGF), and vascular endothelial growth factor (VEGF)

[21,22,23]

JAKs/STATs/Bcl-XL,MYC, survivin, cyclin D1 signaling

[19]

STAT3/S100A8, S100A9/IRF-8 signaling

[24, 25]

Activation

miR-155, miR-21 down-modulate SHIP-1/PTEN and increase STAT3 activation

[26]

NF-κB/IL-1β, IL-6 and TNF-α pathway

[27, 28]

PGE₂/p38 MAPK/ERK/TGF-β

[64, 65]

Immunosuppression

GCN2 kinase, FATP2 and AMPK

[27,28,29,30]

ARG1 utilizes l-arginine as a substrate to produce l-ornithine and urea

[21]

iNOs degrades l-arginine to produce nitric oxide and citrulline

[22]

iNOS prevents IL-2 production in activated leukocytes by impairing the stability of interleukin 2 (IL-2)-encoding mRNA

[24]

MDSCs sequester l-cystine by expressing cystine/glutamate antiporter xCT (XCT; SLC7A11)

[25]

MDSCs induce depletion of tryptophan via indoleamine-pyrrole 2, 3-dioxygenase (IDO) which catalyzes reduction of extracellular l-tryptophan to produce kynurenines

[2]

MDSCs produce RNS or ROS, chemokines, cytokines and other suppressive mediators to blunt TCR signaling and inhibit T cell survival persistent ER stress prolonged immunosuppression effects of MDSCs

[2, 30]