Exosomes from Myeloid-Derived Suppressor Cells Carry Biologically Active Proteins

Myeloid-derived
suppressor cells (MDSC) are present in most cancer patients where
they inhibit natural anti-tumor immunity and are an obstacle to anti-cancer
immunotherapies. They mediate immune suppression through their production
of proteins and soluble mediators that prevent the activation of tumor-reactive
T lymphyocytes, polarize macrophages toward a tumor-promoting phenotype,
and facilitate angiogenesis. The accumulation and suppressive potency
of MDSC is regulated by inflammation within the tumor microenvironment.
Recently exosomes have been proposed to act as intercellular communicators,
carrying active proteins and other molecules between sender cells
and receiver cells. In this report we describe the proteome of exosomes
shed by MDSC induced in BALB/c mice by the 4T1 mammary carcinoma.
Using bottom-up proteomics, we have identified 412 proteins. Spectral
counting identified 63 proteins whose abundance was altered >2-fold
in the inflammatory environment. The pro-inflammatory proteins S100A8
and S100A9, previously shown to be secreted by MDSC and to be chemotactic
for MDSC, are abundant in MDSC-derived exosomes. Bioassays reveal
that MDSC-derived exosomes polarize macrophages toward a tumor-promoting
type 2 phenotype, in addition to possessing S100A8/A9 chemotactic
activity. These results suggest that some of the tumor-promoting functions
of MDSC are implemented by MDSC-shed exosomes.