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

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 those of their parental cells.
Several of these molecules have known or predicted functions consistent
with MDSC suppressive activity, suggesting a potential mechanistic
redundancy.