The monocytic MDSC (M‐MDSC) is one of the major types of MDSCs, which play important roles in suppression of antitumor immunity. However, the mechanisms underlying how M‐MDSCs so heavily accumulate in patients with cancer are still poorly understood. The purpose of this study was to identify miRNAs that regulate the proliferation and differentiation of M‐MDSCs. Microarray analysis was performed to identify differentially expressed miRNAs between tumor‐induced M‐MDSCs (TM‐MDSCs) and their counterparts from tumor‐free mice. The miRNAs and their target genes that regulate the proliferation and differentiation of myeloid cells were predicted by bioinformatics analysis and validated by RT‐qPCR. Luciferase reporter assays were used to analyze the relationships between miRNAs and target genes. Overexpression of candidate miRNAs and target genes in myeloid cells was conducted to verify their functions in cell proliferation, differentiation, and apoptosis. Our data showed that miR‐486 was overexpressed in TM‐MDSCs. Cebpa was predicted to be one of the target genes of miR‐486 that regulates the proliferation of myeloid cells. Expression of Cebpa was inversely correlated with miR‐486 in TM‐MDSCs, and we found that overexpression of miR‐486 suppressed the expression of Cebpa in both 293T cells determined by luciferase reporter assays and in myeloid cells determined by RT‐qPCR. Overexpression of miR‐486 promoted proliferation and suppressed apoptosis in myeloid cells, as opposed to overexpression of Cebpa, which promoted the opposing phenotype. Overexpression of either miR‐486 or Cebpa inhibited differentiation of myeloid cells. This study indicates that miR‐486 promotes proliferation and suppresses apoptosis in myeloid cells by targeting Cebpa in vitro, suggesting that miR‐486 and Cebpa might be involved in the expansion of TM‐MDSCs in tumor‐bearing mice.

Myeloid-derived suppressor cells (MDSCs), one of the major orchestrators of the immunosuppressive network, are associated with immune suppression and considered a prime target for cancer immunotherapy. At present, various strategies have been explored to deplete and/or inactivate MDSCs in vivo. In this study, we investigated the effect of arsenic trioxide (ATO) on MDSCs derived from tumor-bearing mice. This study examined the in vitro and in vivo effects of ATO administration on MDSCs from C57/j mice bearing either the B16 or H22 tumor. The MDSCs were then characterized for phenotype, gene expression and function. Administration with ATO in vitro significantly induced MDSC differentiation, inhibited their proliferation and triggered apoptosis. Treatment with ATO in these murine tumor models significantly inhibited tumor growth and splenomegaly, decreased the percentages of MDSCs in the spleen, promoted their differentiation, reduced tumor necrosis factor-α and interleukin-10 levels and weakened the immune inhibition activity of MDSCs on T cells. In addition, we observed the underlying mechanism involved in the regulation of MDSCs by ATO, which included a panel of cytokines and signaling pathways. The findings showed the immunoregulatory effects of ATO by inducing apoptosis, promoting differentiation and inhibiting the function of MDSCs, suggesting that ATO has potential clinical benefit as it selectively attenuates MDSC-induced immunosuppression.

Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous myeloid cells that can suppress antitumor immunity. MDSCs are divided into granulocytic (G-MDSCs) and monocytic subsets. In the present study, the microRNA profiles of the G-MDSCs were determined and the differential expression of microRNAs between G-MDSCs from tumor-bearing mice and tumor-free mice was examined. The number of G-MDSCs in spleens of Lewis lung carcinoma (LLC)-bearing mice was ~6-fold higher than in spleens of normal mice (13.54±1.74% vs. 2.14±1.44%; P<0.01) and G-MDSCs account for about 72.9% of all MDSCs. The microRNA (miRNA) profiles of the G-MDSCs from spleen of LLC-bearing mice were obtained using a microRNA microarray and compared with their counterparts from spleens of tumor-free mice. A total of 43 miRNAs with >1.3-fold increased or decreased change were differentially expressed between the experimental and control group mice. The levels of nine of these differentially expressed miRNAs, miRNA-468 (miR-486), miR-192, miR-128, miR-125a, miR-149, miR-27a, miR-125b, miR-350 and miR-328, were also analyzed by RT-qPCR to validate the microarray data. The concordance rate between the results tested by the two methods was 88.9%. Bioinformatics analyses revealed that these miRNAs may act on various target genes, including Adar, Pik3r1, Rybp and Rabgap1, to regulate the survival, differentiation and the function of tumor-induced granulocytic MDSCs. The results revealed microRNAs and potential targets that may be vital for regulating survival, differentiation and function of G-MDSCs induced by LLC. Further investigation should be performed to clarify the roles of these microRNAs in regulating LLC-induced granulocytic MDSCs and the target genes that mediate their functions.