Differential Content of Proteins, mRNAs, and miRNAs Suggests that MDSC and Their Exosomes May Mediate Distinct Immune Suppressive Functions

Abstract

Myeloid-derived suppressor cells (MDSC) are immature myeloid cells that accumulate in the circulation and the tumor microenvironment of most cancer patients. There, MDSC suppress both adaptive and innate immunity, hindering immunotherapies. The inflammatory milieu often present in cancers facilitates MDSC suppressive activity, causing aggressive tumor progression and metastasis. MDSC from tumor-bearing mice release exosomes, which carry biologically active proteins and mediate some of the immunosuppressive functions characteristic of MDSC. Studies on other cell types have shown that exosomes may also carry RNAs which can be transferred to local and distant cells, yet the mRNA and microRNA cargo of MDSC-derived exosomes has not been studied to date. Here, the cargo of MDSC and their exosomes was interrogated with the goal of identifying and characterizing molecules that may facilitate MDSC suppressive potency. Because inflammation is an established driving force for MDSC suppressive activity, we used the well-established 4T1 mouse mammary carcinoma system, which includes “conventional” as well as “inflammatory” MDSC. We provide evidence that MDSC-derived exosomes carry proteins, mRNAs, and microRNAs with different quantitative profiles than that of their parental cells. Several of these molecules have known or predicted functions consistent with MDSC suppressive activity, suggesting a potential mechanistic redundancy.

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

“…The production of IL-10 is further upregulated by HMGB1 [24,47]. MDSCs have the capacity to produce TGF-β [48], either as secreted or as membrane-bound protein, by means of which they render natural killer (NK) cells inactive, whilst facilitating the accumulation and induction of Tregs, which further induce the effector T cell suppression against the progression of cancer [2,6,24,49]. Some researchers also demonstrated the interaction between CD8/Tc17 and CD4/Th17 cells, with IL-17R expressing MDSCs [50].…”

“…Another modus operandi that MDSCs seem to exploit in order to exert immunosuppression is the release of exosomes. The exosomal cargo of MDSCs is rather rich in multiple molecules (e.g., cytokines and growth factors), which exert certain suppressive and tumor-favoring functions [25,36,49]. Apart from some anti-inflammatory mediators (TGF-β, IL-10, S100A8/A9, HMGB1, MMPs), they also contain small RNA molecules known as micro RNAs (miRNAs) that either induce other MDSCs to exert immunosuppressive functions (e.g., miR-210, responsible for the expression of ARG1) or aid in the process of angiogenesis (e.g., miR-126a) [25,36,49].…”

“…The exosomal cargo of MDSCs is rather rich in multiple molecules (e.g., cytokines and growth factors), which exert certain suppressive and tumor-favoring functions [25,36,49]. Apart from some anti-inflammatory mediators (TGF-β, IL-10, S100A8/A9, HMGB1, MMPs), they also contain small RNA molecules known as micro RNAs (miRNAs) that either induce other MDSCs to exert immunosuppressive functions (e.g., miR-210, responsible for the expression of ARG1) or aid in the process of angiogenesis (e.g., miR-126a) [25,36,49]. Recent studies have demonstrated that MDSCs express immune checkpoint regulators, and especially programmed-death ligand 1 (PD-L1), which binds to programmed death 1 receptor (PD-1) [1,2,55,56].…”

“…The general crosstalk between MDSCs (either by secretion of soluble factors or by exosomes) and cancer cells results into the production of pro-angiogenic factors (VEGF, MMP, miRNA-126α), preparing the way for cancer cells to metastasize [3,5,6,49]. The interaction of IL-28 with tumor cells can promote the epithelial to mesenchymal transition (EMT) of the cancer cells, making the latter more invasive, since it also upregulates the expression of VEGF by tumor cells in canine mammary cancer cells [54].…”

Decoding communication patterns of the innate immune system by quantitative proteomics

“…These include HMG B1 (a proinflammatory mediator and driver of MDSC accumulation and suppressive potency), providing a connection among MDSC exosome profiles, ubiquitination, and the immunosuppressive roles of MDSC . Other examples of proteomic profiling of MDSCs include an integrative study investigating the protein, mRNA, and miRNA (microRNAs) contents of conventional and inflammatory MDSC and MDSC‐derived exosomes . Here, RNA cargo also mediates MDSC immunosuppressive activity, suggesting a potential mechanistic redundancy between functional proteins and RNAs.…”