Tumor-Promoting Effects of Myeloid-Derived Suppressor Cells Are Potentiated by Hypoxia-Induced Expression of miR-210

Abstract

Myeloid-derived suppressor cells (MDSC) contribute significantly to the malignant characters conferred by hypoxic tumor microenvironments. However, selective biomarkers of MDSC function in this critical setting have not been defined. Here, we report that miR-210 expression is elevated by hypoxia-inducible factor-1a (HIF1a) in MDSC localized to tumors, compared with splenic MDSC from tumor-bearing mice. In tumor MDSC, we determined that HIF1a was bound directly to a transcriptionally active hypoxia-response element in the miR-210 proximal promoter. miR-210 overexpression was sufficient to enhance MDSC-mediated T-cell suppression under normoxic conditions, while targeting hypoxia-induced miR-210 was sufficient to decrease MDSC function against T cells. Mechanistic investigations revealed that miR-210 modulated MDSC function by increasing arginase activity and nitric oxide production, without affecting reactive oxygen species, IL6, or IL10 production or expression of PD-L1. In splenic MDSC, miR-210 regulated Arg1, Cxcl12, and IL16 at the levels of both mRNA and protein, the reversal of which under normoxic conditions decreased T-cellsuppressive effects and IFNg production. Interestingly, miR-210 overexpression or targeting IL16 or CXCL12 enhanced the immunosuppressive activity of MDSC in vivo, resulting in increased tumor growth. Taken together, these results provide a preclinical rationale to explore miR-210 inhibitory oligonucleotides as adjuvants to boost immunotherapeutic responses in cancer patients.

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

“…Some of the chemokines were not specific to granulocytes and could recruit monocytic cells and macrophages. More detailed studies were performed with Cxcl-1, which plays a major role in recruitment of neutrophils and PMN-MDSC to tumor site (Noman et al, 2015; Obermajer et al, 2011). Proteins concentrations were measured in LLC tumor lysates at different times during the treatment.…”

The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200

“…10,11 RNA isolation and SYBR-GREEN qRT-PCR (real timequantitative polymerase chain reaction) and Western blot RNA isolation and SYBR-GREEN qRT-PCR were performed as described. 12 Expression level of 18S was used as endogenous control. Western blotting was performed as previously.…”

Metabolic regulation of immune responses: therapeutic opportunities

“…HIF1α protein is induced following the inhibition of the prolyl-hydroxylases that target HIF1α for degradation. HIF1α can also promote the expression of molecules that have immunosuppressive effects in myeloid cells, including miR-210 and PD-L1 (107,108). In fact, depending on the context, HIF1α can promote proinflammatory or antiinflammatory functions of myeloid cells (26,(107)(108)(109)(110).…”

“…HIF1α can also promote the expression of molecules that have immunosuppressive effects in myeloid cells, including miR-210 and PD-L1 (107,108). In fact, depending on the context, HIF1α can promote proinflammatory or antiinflammatory functions of myeloid cells (26,(107)(108)(109)(110). Succinate can also have proinflammatory effects through ligating the succinate receptor 1 (SUCNR1) to augment DC chemotaxis to enhance DC-induced T cell responses (111,112).…”