MDSCs are a heterogeneous population derived from bone marrow progenitor cells and immature myeloid cells (1). In normal physiology, immature myeloid cells are differentiated into monocytes, granulocytes, macrophages and dendritic cells, which exert immune activity (2). However, in cancers and other diseases (such as inflammation), MDSCs have the negative regulatory immune response to exacerbate disease status (2, 3). In the process of tumor progression, MDSCs cannot properly differentiated into monocytes and macrophages to play their immune roles, but abnormally proliferate and accumulate within TME (4). Tumor cells secrete many factors to inhibit the differentiation of immature myeloid cells and promote the proliferation and immunosuppressive roles of MDSCs (5). These mediators mainly include the TGF-β, Ligands for toll-like receptors, IL-1β, IFN-γ, IL-6, FMS-like tyrosine kinase 3 ligand (FLT3L), Granulocyte colony-stimulating factor (G-SCF), Macrophage colony-stimulating factor (M-CSF), Granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4 (6). Most mediators activate the functional state of MDSCs by regulating signal converters and transcriptional activators (STATs and NFκB) (7, 8). For example, IL-6 enhances both stimulatory and inhibitory roles of MDSCs via STAT3 signaling pathways in breast cancer (8, 9).

Tumor MDSCs are mainly divided into two main subtypes according to their phenotypes and origins, which are defined by cell surface markers of MDSCs in both tumor models and cancer patients (10, 11). The phenotypes of MDSCs in tumor-bearing mice are defined using Gr1 (ly6G/ly6C)/CD11b and further include two subtypes of MDSCs: Monocyte-MDSCs (M-MDSCs, CD11b+Ly6G−Ly6Chi) and Granulocyte-MDSCs (G-MDSCs, CD11b+Ly6G+Ly6Clo) (12, 13). The phenotypes of MDSCs are more diverse in cancer patients. MDSCs are cell populations expressing Lin-HLA-DR-CD33+ or CD11b-CD14-CD33+ in human body. The main subtypes are also divided into M-MDSCs (HLA-DR−/loCD11b+CD14+ CD15−) and G-MDSCs (CD11b+ CD14− CD15+ or CD11b+CD14− CD66b+) (14). Third subtype known as early-MDSCs which has been found in human studies. They are defined as Lin-HLA-DR-CD33+, mainly consisting of colony-forming cells activity and other myeloid precursor cells (13, 15).

M-MDSCs account for about 80% of all tumor MDSCs, but their inhibitory roles are lower than those of G-MDSCs. M-MDSCs are modulated by producing NO and Arginases. In contrast, the roles of G-MDSCs are determined by ROS and H2O2 (16–19). The main function of G-MDSCs is to inhibit T cell function, while M-MDSCs mainly differentiate into TAMs in cancer. It is well known that MDSCs have become the most important prognostic markers in cancer immunotherapy and contribute to immunosuppressive checkpoint resistance (20) ( Figure 1 ).

MiRNAs are non-coding single-stranded small RNAs of approximately 22-24 nucleotides in length and are highly conserved evolutionarily, and are widely found in eukaryotic cells. They play vital regulatory roles in cells, especially in mRNA post-transcriptional regulation, and reduce mRNA expression levels by binding to the 3’UTR of mRNA and binding to the 5 ‘-UTR of mRNA to upregulate its transcription (10–12). MiRNAs are involved in regulating both a wide range of physiological activities such as cell cycle, differentiation, proliferation, maturation and immune response and pathological processes, such as inflammation and cancer (13). For example, our data have shown that miRNAs mediate the differentiation, expansion and function of tumor MDSCs (14).

LncRNAs are non-protein-coding RNAs of approximately 200 nucleotides in length (15). According to the position of lncRNAs in the genome relative to protein-coding genes, they can be divided into five categories: sense, antisense, bidirectional, intronic and intergenic (16, 17). LncRNAs are ever regarded byproducts of RNA polymerase II transcription as “noise” of genomic transcription without biological function (5, 17). However, the increasing evidences have revealed that LncRNAs mediate gene expression through chromatin modification, transcriptional regulation and post-transcriptional regulation in the nucleus and extranuclear, and are also involved in the occurrence and development of tumors (18–22) ( Figure 2 ). LncRNAs have been found to mediate the carcinogenesis of colon cancer through a variety of molecular mechanisms, suggesting that lncRNAs can be used as biomarkers for early diagnosis and treatment of colon cancer (23). LncRNAs are overexpressed during the development, differentiation and activation of immune cells, such as monocytes, macrophages, dendritic cells, neutrophils (24). Furthermore, the increasing data were conducted on the activity of lncRNAs on MDSCs in TME (16, 25–27). Both miRNA and lncRNAs, as Non-coding RNAs (ncRNAs) can modulate tumor MDSCs. Thus, here we discuss the regulatory mechanisms of miRNAs/lncRNAs on the biological status and immune activity of MDSCs in TME, and put forward our own opinions.

ncRNAs are mainly divided by length into small (< 200 nucleotides) and long (> 200 nucleotides) RNAs according to base length. ncRNAs are: miRNAs、lncRNAs、snRNAs、circRNAs (28). ncRNAs act as regulatory molecules that regulate for a wide range of cellular processes, such as chromatin remodeling, transcription and post-transcriptional modification (29). MiRNAs have been well investigated over the past decade, lncRNAs are actively studied for their diverse roles in gene expression regulation. Besides, lncRNAs themselves can interact with other ncRNAs, such as miRNAs (30). Both miRNA and lncRNA are transcribed by RNA polymerase II, and they play important roles in gene expression under both physiological and pathological conditions, as transcriptional and post-transcriptional regulators (28). Studies have shown that miRNAs and lncRNAs are involved in transcriptional regulation at different levels, miRNAs/lncRNAs directly determine gene expression by binding with mRNA, gene/transcript or histone modifiers (31). LncRNAs may play a functional role as miRNA sponges by base-pair blocking of miRNA binding to target mRNA-3’UTR (32) ( Figure 3 ).

Recent studies have highlighted the diverse roles of MiRNAs/LncRNAs in cancer progression and metastasis. Increasing numbers of miRNAs and lncRNAs are found to be dysregulated in cervical cancer, regulating metastasis through regulating metastasis-related genes and signaling pathways. Moreover, miRNAs can interact with lncRNAs respectively during this complex process (33, 34). In breast cancer, the lncRNA MALAT1 and miR-100 are indirectly interlinked through VEGFA. MALAT1 binds to miR-216b as a competing endogenous RNA to restore Pyridox(am)ine-5- phosphate Oxidase deficiency (PNPO) and promote cell proliferation, migration and invasion in breast cancer (33). Therefore, miRNAs/lncRNAs are involved in gene expression and transcriptional regulation. They also affect the development of cancer and regulate the expression of oncogenes and tumor suppressors in TME (28, 32, 35). Therefore, the regulation of miRNA/lncRNA is more conducive to the research of bioactive targets for cancer treatment.

Researchers have found that the interactions between miRNAs/LncRNAs and transcription factor modulated the biological status and immune activity of MDSCs in TME (36). Here, we describe the regulation of miRNA/lncRNA on MDSCs in the TME. The abnormal expression of miRNAs/lncRNAs in MDSCs and their regulatory mechanism on MDSCs have become potential breakthrough points.

Exosomes are small extracellular vesicles with size 30-150nm in diameter that are secreted by most cells (72). Exosomes are rich in genetic material and molecules: DNA, miRNA, lncRNAs, proteins and lipids, which are essential for cell-cell communication and physiological status. Moreover, exosomes are also involved in the regulation of tumor progression in the TME (11). Recently, it has been demonstrated that exosomes secreted by tumor cells play critical roles in cancer progression and invasion, including TME remodeling, tumor metastasis and tumor-associated immunosuppression (73).

MiRNAs in tumor-derived exosomes mediate the activity of MDSCs in TME through different expression patterns, transcription factors and signaling pathways (61, 74). In pancreatic cancer, the increased expression of miR-let-7i in TDEs affects the levels of myeloid inhibitory intracellular inflammatory cytokines (IL-6, IL-17, IL-1β) and transcription factors, downregulating the anti-tumor immune response (74). In glioma, glioma-derived exosomes (GDEs) miR-29a and miR-92a increase the proliferation and suppressive roles of MDSCs through targeting high-mobility group box transcription factor 1 (Hbp1) and protein kinase cAMP-dependent type I regulatory subunit alpha (Prkar1a), respectively, further mediating the formation of suppressive TME (75). In LLC lung cancer model, miR-21a from LLC-Exosomes are revealed to increase both the autocrine production of IL-6 and phosphorylation levels of STAT3 by targeting Programmed cell death 4(PDCD4), thereby preventing the activation of cytotoxic CD8+T cells and enhancing the proliferation and activity of MDSCs (76). In addition, in hypoxia-induced GDEs miR-10a and miR-21 stimulate the expansion and activation of MDSCs by targeting RAR-related orphan receptor α (RORA) and PTEN (77). In breast cancer with high expression of interleukin-6, TDEs miR-9 and miR-181A activate the JAK/STAT to exaggerate the proliferation and inhibitory roles of MDSCs by targeting SOCS3 and PIAS3 (76). In gastric cancer, Ren et al. found that the TDE miR-107 prompted the proliferation and activation of MDSCs by targeting Dicer1 and PTEN (78) ( Table 3 ).

lncRNAs are also secreted in exosomes as messengers of intercellular communication. Some lncRNAs are enriched in exosomes, while others are almost absent, suggesting that some lncrnas are selectively trafficked into exosomes. Furthermore, RNA sequencing in exosomes derived from tumors revealed that most of the non-coding transcripts of exosomes were lncRNAs (79). Meanwhile, exosomal LncRNAs are often found in clinical cancer samples, indicating that LncRNA may be a potential biomarker for cancer diagnosis. In primary urothelial bladder cancer (UBC) cells, exosomic lncRNA HOTAIR is secreted by proteins (SNAI1, TWIST1, ZEB1 and LAMB3), which regulate EMT, resulting in gene changes on epithelial cells. LncRNA ZFAS1 is found to increase in the serum exosomes of GC patients with gastric cancer (GC), suggesting that lncRNA ZFAS1 plays a positive role in the progression of gastric cancer (80). Exosomal LncRNA ZFAS1 also promotes the proliferation, migration and invasion of tumor cells from esophageal carcinoma (ESCC), and inhibits the apoptosis of ESCC cells by up-regulating STAT3 and down-regulating MiR-124, leading to the carcinogenesis of ESCC. LncRNA ZFAS1 is believed to be a competitive endogenous RNA regulating MiR-124, thereby enhancing STAT3 expression (81). In bladder cancer (BCs), lncRNA-PTENP1 is found to be reduced in tissues and plasma exosomes. Cells which secrete exosomal PTENP1, deliver it to BC cells to inhibit the biological malignant behavior of BC cells by increasing apoptosis and decreasing invasion and migration (82). The regulatory mechanism of TDEs lncRNAs on MDSCs has not been clarified thoroughly. A few studies have shown that TDEs lncRNAs play the important regulatory role in TME and tumor cell interactions, accelerating tumor growth (24). TDEs lncRNAs are transported to the TME to modulate the roles of various cells, including macrophages, endothelial cells and fibroblasts (24). In liver cancer cells, lncRNA TUC339 induces M2 polarization by interacting with cytokine-cytokine receptors to exaggerate tumor metastasis (83). It is well known that lncRNA urothelial carcinoma-associated (UCA1) is an lncRNA associated with the occurrence and progression of various cancers, including colorectal cancer. Meanwhile, the mechanism of tumor-derived exosome lncRNA-UCA1 has also been studied. In colon cancer (CRC), UCA1 plays a key role in CRC tumor progression by packaging into exosome, and UCA1 sequesters mir-143 via a sponge mechanism (84) ( Table 4 ). However, the mechanism by which exosome miRNA/LncRNA affects MDSC in TME remains to be studied.

LncRNA not only directly participates in the regulation of gene expression, but also regulates the expression of miRNA (85). miRNA can regulate mRNA expression through the miRNA response elements (MREs) of mRNA 3 ‘- UTR. LncRNA can adsorb miRNA through MREs to competitively bind miRNA as one Competing endogenous RNA (ceRNA) and interfere with the binding of miRNA with downstream target genes, and then participate in various biological processes such as cell proliferation, differentiation, apoptosis and angiogenesis (86, 87). Luan et al. reported that LncRNA XLOC_006390z played a functional role as one ceRNA in cervical cancer. When XLOC_006390 is knocked out, the expression of Mir-331-3p target gene NRP2 and Mir-338-3p target gene PKM2 is significantly downregulated, further promoting the occurrence and metastasis of cervical cancer (88). MiRNA can regulate lncRNA expression as well as target mRNA expression. LncRNA structure is similar to mRNA. LncRNAs indirectly inhibit the negative regulation of miRNAs on target genes by competing with miRNA to bind the 3’-UTR of target gene mRNA. Some of lncRNAs can form miRNA precursors through intracellular shearing, and then process and generate specific miRNAs to regulate the expression of target genes and exert functions. In addition, Individual lncRNAs function as endogenous miRNA sponges and inhibit miRNA expression, further performing biological roles. Therefore, integrated analysis of the regulatory relationship between mirNA-lncrNA-mrna can explain the occurrence and development of diseases comprehensively. These indicted that miRNA may regulate lncRNA expression through the similar mechanism by which mRNA is regulated ( Figure 8 ).

Mir-155 was overexpressed in MEGO1 leukemia cell line and the expression level of target lncRNA was significantly decreased. When Mir-155 was silenced, the expression of target lncRNA was significantly increased. These results indicated that miRNA could regulate the expression of lncRNA (89). lncRNAs can act as one ceRNA to sequester miRNAs, regulating the abundance and activity of miRNAs, resulting in the de-repression of genes targeted by corresponding miRNAs in cancer progression (34, 90). Recently, the regulation of lncRNA/miRNA in MDSCs has become increasingly important. Studies have speculated that lncRNA-miRNA may have synergistic effects on the roles of MDSCs. MiR-9 and or Runx1 overlapping RNA (RUNXOR) are two non-coding RNAs involved in the differentiation and activation of MDSCs. Tian et al. showed that miR-9 directly downregulated the expression of lncRNA Runx to stimulate the differentiation of MDSCs and reduce the suppressive ability of MDSCs (36). The retinal non-coding RNA3 (RNCR3), an intragenic lncRNA, which is conserved sequence in mammalian genomes, has been shown to be highly expressed in glioblastoma and prostate cancer (91). Furthermore. Shang et al. recognized that RNCR3 expression in MDSCs is upregulated by inflammatory and tumor associated factors. In the TME, the expression of RNCR3 was up-regulated in MDSC. RNCR3 may function as one ceRNA to upregulate the expression of Arg-1 and iNOS on MDSCs to enhance the roles of these MDSCs through sponge mir-185-5p which binds to CHOP to upregulate CHOP expression [104]. Therefore, those results suggest that RNCR3/miR-185-5p/Chop may strengthen suppressive roles of MDSCs in the TME.

MDSCs, as immunosuppressive cells, seriously affect the progression, invasion and metastasis of tumors, and may be used as potential targets for tumor immunotherapy. The regulatory mechanism of tumor MDSCs has been widely investigated by us and other scientists (14, 92–95). Increasing evidence demonstrated that ncRNAs, especially miRNA and lncRNAs, played the key roles in the regulation of tumor MDSCs in the TME. Here we review that MiRNA/lncRNAs regulate the biological status and functional activity of tumor MDSCs through different regulatory mechanisms. Moreover, we discuss how both exosomal miRNAs/lncRNAs and the interaction of miRNAs/lncRNAs modulate tumor MDSCs. However, In the TME, the regulation of miRNAs/lncRNA on MDSCs is affected. It remains to be explored how those dysregulated miRNAs/lncRNA are combined in the TME to act on tumor MDSCs through tumor-related signaling pathway. In addition, the regulation of miRNA/lncRNAs on MDSCs provided opportunities and challenges for targeting MDSCs immunotherapy. Moreover, these functional data of miRNA/lncRNA on tumor MDSCs are gained from animal studies, there are a few data from human patients with cancer. Thus, miRNAs/lncRNAs application for tumor MDSCs in clinical patients with cancer need be further clarified. In summary, the interaction of dysregulated miRNAs/lncRNA on tumor MDSCs with transcription factors, cofactors and chromatin modifiers may target specific signals to treat tumor MDSCs in the TME, providing novel strategies for cancer treatment.

XL and SZ wrote, reviewed, and revised manuscript, figures and tables.HS prepared the figures and tables. HL and MY reviewed and revised the manuscript. YS revised the manuscript. PQ wrote, reviewed, and revised manuscript, figures and tables. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (Grant No. 81572868) and Science Foundation of Shandong (Grant No. ZR2018LC012).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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