Myeloid-derived suppressor cells in gastrointestinal cancers: A systemic review

Table 1 Two main categories of myeloid-derived suppressor cells and their immunosuppressive functions[59]

Type of MDSC	Markers in humans	Immunosuppression mediator	Mechanism of immunosuppression
PMN-MDSCs	CD11b+CD14−CD15+HLADR− or CD11b+CD14−CD66b+ or LOX-1+	ARG1, ROS	Suppressing immune responses mainly in an antigen-specific manner; ROS production
M-MDSCs	CD11b+CD14+CD15−HLADRlow/−	NO, ARG1, and cytokines such as TGF-β and IL-10	Suppressing T cell responses, both in antigen-specific and non-specific manners; production of NO and cytokines

ARG1: Arginase 1; IL-10: Interleukin-10; M-MDSCs: Monocytic myeloid-derived suppressor cells; NO: Nitric oxide; PMN-MDSCs: Polymorphonuclear myeloid-derived suppressor cells; ROS: Reactive oxygen species; TGF-β: Transforming growth factor-beta; MDSC: Myeloid-derived suppressor cell.

Table 2 Potential therapeutic strategy for targeting myeloid-derived suppressor cells

Strategy	Agents
Blocking TDFs from being produced or from reaching the bone marrow	Targeting the IL-6 receptor (tocilizumab)[83]
Key cytokines, such as IL-6 or S100A8/A9, could be directly targeted[82,84]
Inhibiting generation of MDSCs from bone marrow progenitors or inducing apoptosis of circulating MDSCs[6]	Gemcitabine, 5-fluorouracil, sunitinib, and zolendronate[84]
Preventing trafficking of myeloid cells from the marrow to peripheral lymphoid organs or to the tumor microenvironment[6]	Drugs targeting chemokines CXCR2, CXCR4, and CSF1R[14]
Directly blocking MDSC suppression of T cells[85]	Phosphodiesterase type 5 inhibitors, e.g., sildenafil and tadalafil, or cyclooxygenase 2 inhibitors[63]
Drugs that would promote differentiation of MDSCs into proficient antigen-presenting cells that can stimulate tumor-specific T cells and/or into mature leukocytes[85]	All-trans retinoic acid, vitamin D3, and the DNA-methylating agent 5-azacytidine[85]

MDSCs: Myeloid-derived suppressor cells; CSF1R: Colony-stimulating factor 1 receptor; CXCR2: C-X-C motif receptor 2; CXCR4: C-X-C motif receptor 4; IL-6: Interleukin-6; TDFs: Tumor-derived factors.