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Diab et al. J Cancer Metastasis Treat 2022;8:42 https://dx.doi.org/10.20517/2394-4722.2022.60 Page 5 of 14

Figure 2. Myeloid cell lineage differentiation and markers. HSC: Hematopoietic stem cells; CMP: common myeloid progenitors; MDSC:
myeloid-derived suppressor cell; TAM: tumor-associated macrophage; PMN-MDSC: polymorphonuclear MDSC; M-MDSC: monocytic
MDSC [29] .

levels in M-MDSCs and dimly in PMN-MDSCs [31,32] . Additionally, CD15 or CD66b can be used as a marker
for PMN-MDSCs [31,32] .

[33]
MDSCs exert their immune suppressive functions through multiple mechanisms . MDSCs release both
reactive oxygen species (ROS) and reactive nitrogen species (RNS), which inhibit T cells fitness,
[33]
proliferation and migration within the TME . MDSCs produce high levels of Arginase 1 and indoleamine
2,3-dioxygenase 1, which metabolize L-arginine and L-tryptophan, respectively, and lead to effector T cell
suppression . Additionally, MDSCs induce T cell tolerance through the expression of inhibitory receptors
[33]
such as the PD-L1 and CTLA-4 receptors, as well as sustain the development of Tregs through the CD40
[34,35]
engagement in the presence of interleukin-10 (IL-10) and TGF-β . MDSCs produce HB-EGF, an EGFR
[36]
ligand, which activates EGFR/MAPK signaling in tumor cells and leads to increased PD-L1 expression .
Activated NF-κB promotes the functions of MDSCs through the production of colony-stimulating factors
such as GM-CSF, as well as the secretion of chemokines, such as CXCL1, 2, and 5 that recruit CXCR2
+
MDSCs to the TME [37,38] . The frequency of tumor-infiltrating T cells correlates inversely with the presence of
MDSCs . MDSCs also promote tumor progression through non-immune processes, including tumor
[33]
[34]
angiogenesis through the secretion of vascular endothelial growth factor (VEGF) .
Due to their tumor-promoting nature, restraining the expansion or functions of MDSCs is an interesting
therapeutic target. Decreased tumor growth and increased effector T cell infiltration were observed in GM-
CSF knock-down mouse grafts . Similar results were observed through the depletion of PMN-MDSCs
[39]
using a Ly6G-targeting antibody in mouse models . In another mouse model, inhibition of CXCR2, which
[40]
is upregulated in MDSCs and regulates their recruitment to the TME, resulted in reduced metastatic
potential, synergy with immunotherapy, and improved survival .
[41]
TAMs
[42]
Macrophages arise from tissue-resident as well as bone marrow-derived macrophages . They are linked to
poor survival . Tissue-resident macrophages originate from embryonic precursors or adult hematopoietic
[43]