Transcriptomic Analyses of Myeloid-Derived Suppressor Cell Subsets in the Circulation of Colorectal Cancer Patients

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.

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

“…However, since these cells also expressed antigen-presenting proteins (HLA-DR) and costimulatory molecules (CD86), it is unclear whether they have pro-tumour or antitumour functions and whether they may have any relationship with PMN-MDSCs 25 . In a recent study in patients with colon cancer, PMN-MDSCs showed upregulation of several pathways associated with DNA damage responses, chemotaxis, apoptosis, MAPK signalling, TGFβ signalling and various myeloid differentiation-related transcripts compared with monocytic antigen-presenting cells (APCs) or early MDSCs 26 . Furthermore, PMN-MDSCs had an elevated expression of genes related to Janus kinase (JAK) and STAT signalling.…”

“…Additionally, the authors found that pathways involving phosphatidylinositol 3-kinase (PI3K), IL-6 and TGFβ were upregulated in M-MDSCs and cell cycle-related pathways were upregulated in early MDSCs compared with in monocytic APCs. Importantly, acetylation-related genes were upregulated in both PMN-MDSCs and M-MDSCs, indicating that epigenetic modifications may also play a role in the regulation of multiple tumour-promoting genes in PMN-MDSCs and M-MDSCs 26 .…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…For example, PMN-MDSCs can upregulate nicotinamide adenine dinucleotide phosphate (NADP) oxidase and activate STAT-3 to generate ROS, while M-MDSCs can modulate inducible nitric oxide synthase and activate STAT1 to release NO to suppress the function of T lymphocytes. 172 , 173 Notably, MDSCs can inhibit not only the acquired antitumor immune response but also the innate antitumor immune response. 174 , 175 For instance, MDSCs can impair the antigen presentation of DCs and phagocytosis of NK cells to promote tumor immune escape.…”

Myeloid-Derived Suppressor Cells in Solid Tumors

“…The higher level of M-MDSCs in OC patients indicated shorter recurrence-free survival. G-MDSCs are usually elevated in terminal cancer patients [ 173 , 174 , 175 ], accompanied by poor physical status and prognosis. In light of the differences between these two subgroups of MDSCs, it is necessary to consider their respective characteristics at different stages of the disease, which would be meaningful for predicting the development of cancer and evaluating the response of cancer patients to immunotherapy.…”