Abstract
Myeloid-derived suppressor cells (MDSCs) promote tumor immune evasion and favor tumorigenesis by activating various tumor-promoting downstream signals. MDSC expansion is evident in the circulation and tumor microenvironment of many solid tumors including colorectal cancer (CRC). We have recently reported the transcriptomic profiles of tumor-infiltrating MDSCs in CRC patients and uncovered pathways, which could potentially assist tumor progression. In this study, we sorted different subsets of circulating MDSCs in CRC patients and investigated their transcriptomic profiles in order to disclose pathways, which could potentially contribute to disease progression. The sorted subsets included polymorphonuclear/granulocytic MDSCs (PMN-MDSCs), immature MDSCs (I-MDSCs), and monocytic MDSCs (M-MDSCs). Our functional annotation analyses revealed that multiple pathways including DNA damage-, chemotaxis-, apoptosis-, mitogen-activated protein kinase-, transforming growth factor β-, and myeloid differentiation–related transcripts were higher in PMN-MDSCs, compared with monocytic antigen-presenting cells (APCs) or I-MDSCs. Furthermore, genes related to Janus kinase (JAK)–signal transducer and activator of transcription (STAT) were also elevated in PMN-MDSCs. These data suggest that upregulation of JAK-STAT pathway could trigger multiple downstream targets in PMN-MDSCs, which favor tumor progression. Additionally, we found that pathways including phosphatidyl inositol 3-kinase (PI3K), interleukin 6, and TGF-β in M-MDSCs and cell cycle–related pathways in I-MDSCs were upregulated, compared with monocytic APCs. Moreover, acetylation-related genes were upregulated in both PMN-MDSCs and M-MDSCs. This latter finding implicates that epigenetic modifications could also play a role in the regulation of multiple tumor-promoting genes in PMN-MDSCs and M-MDSCs. Taken together, this study reveals various signaling pathways, which regulate the function of MDSC subsets in the circulation of CRC patients. However, functional studies are warranted to support these findings.
Highlights
Colorectal cancer (CRC) ranks second in terms of mortality and third in terms of incidence among all cancers in 2018 [1]
We have previously reported that the levels of PMN-Myeloid-derived suppressor cells (MDSCs) and immature MDSCs (I-MDSCs) are higher in the colorectal cancer (CRC) tumor microenvironment (TME) [3]
We found that various signaling pathways, including Janus kinase (JAK)-signal transducer and activator of transcription (STAT), chemotaxis, and histone acetylation, were upregulated in PMN-MDSCs compared with monocytic antigen-presenting cells (APCs): PI3P kinase, PI3 kinase, apoptosis, H3 acetylation, IL-6, and TGF-β pathways were upregulated in monocytic MDSCs (M-MDSCs), and cell cycle–related pathways were upregulated in I-MDSCs compared with monocytic APCs
Summary
Colorectal cancer (CRC) ranks second in terms of mortality and third in terms of incidence among all cancers in 2018 [1]. Myeloid-derived suppressor cells (MDSCs) play a predominant role in the survival of tumor cells by providing an immunosuppressive shield to protect them from host immune response and facilitate resistance to immunotherapy [4]. Increase in circulating MDSC in higher stages of cancer has been reported to be correlated with worse survival rates and resistance to immune checkpoint blockade [7,8,9]. These reports suggest that targeting MDSCs improves the host-immune responses against malignant cells and enhances the efficiency of immune checkpoint blockade therapy
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