Abstract
BackgroundIncreased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients. They play central roles in tumor immune evasion and tumor metastasis. However, limited data are available on phenotypic/transcriptomic characteristics of the different MDSCs subsets in cancer. These cells include immature (I-MDSCs), monocytic (M-MDSCs), and polymorphonuclear/granulocytic (PMN-MDSCs).MethodsPhenotypic characterization of myeloid subsets from 27 colorectal cancer (CRC) patients was assessed by flow cytometric analyses. RNA-sequencing of sorted I-MDSCs, PMN-MDSCs, and antigen-presenting cells (APCs) was also performed.ResultsWe found that the levels of I-MDSCs and PMN-MDSCs were increased in tumor tissues (TT), compared with normal tissues (NT) in colorectal cancer. Our functional annotation analyses showed that genes associated with histone deacetylase (HDAC) activation- and DNA methylation-mediated transcriptional silencing were upregulated, and histone acetyl transferase (HAT)-related genes were downregulated in tumor-infiltrating I-MDSCs. Moreover, pathways implicated in cell trafficking and immune suppression, including Wnt, interleukin-6 (IL-6), and mitogen-activated protein kinase (MAPK) signaling, were upregulated in I-MDSCs. Notably, PMN-MDSCs showed downregulation in genes related to DNA methylation and HDAC binding. Using an ex vivo model, we found that inhibition of HDAC activation or neutralization of IL-6 in CRC tumor tissues downregulates the expression of genes associated with immunosuppression and myeloid cell chemotaxis, confirming the importance of HDAC activation and IL-6 signaling pathway in MDSC function and chemotaxis.ConclusionsThis study provides novel insights into the epigenetic regulations and other molecular pathways in different myeloid cell subsets within the CRC tumor microenvironment (TME), giving opportunities to potential targets for therapeutic benefits.
Highlights
Increased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients
MDSCs express myeloid markers but lack expression of MHC class II molecule, HLA-DR, and are mainly divided into three phenotypically distinct subpopulations; CD33+HLA-DR−/lowCD14−CD15− early-stage, or immature MDSCs (e-MDSC/I-MDSC), which consist of immature myeloid progenitors; CD33+HLA-DR−/lowCD14+CD15− monocytic MDSCs (MMDSCs), which represent suppressive monocytes; and CD33+HLA-DR−/lowCD14−CD15+ polymorphonuclear or granulocytic MDSCs (PMN-MDSCs or G-MDSCs), which are phenotypically distinct from mature neutrophils and possess strong suppressive activity [3, 5,6,7]
Elevated levels of PMN-MDSCs and I-MDSCs in Colorectal cancer (CRC) tumor tissues It has been reported that tumor-infiltrating PMNMDSCs and I-MDSCs are expanded in colorectal tumor tissue, compared with normal colon tissue [13]
Summary
Increased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients. They play central roles in tumor immune evasion and tumor metastasis. Limited data are available on phenotypic/transcriptomic characteristics of the different MDSCs subsets in cancer. These cells include immature (I-MDSCs), monocytic (M-MDSCs), and polymorphonuclear/ granulocytic (PMN-MDSCs). The number of circulating MDSCs has been positively correlated with poor prognosis and low survival rates in cancer patients, including those with CRC [13,14,15]. Further insights into these mechanisms could provide potential candidates to target MDSC populations in cancer
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