Myeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME.
In this study, researchers at Augusta University isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. They observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Their in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. The researchers confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. They also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. These results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.
Schematic diagram showing process of biogenesis of exosomes from MDSCs and role of MDSC-derived exosomes in tumor progression and immunosuppression by AICD
Exosomes secreted from the MDSCs contain pro-tumorigenic factors from the parent cells and can play a crucial role in immunosuppression, tumor growth, angiogenesis, invasion and metastasis by dispensing their contents to the other TME cells or distant cells. MDSC-derived exosomes can activate CD8+ T-cellsand TCR triggering causes activation of DUOX-1 that leads to H2O2 production and eventually generation of ROS in mitochondria. Prolonged TCR stimulation triggers over expression of both Fas (receptor) and FasL (ligand) which culminates in fratricide (from direct cell contact) or autocrine suicide (interaction of soluble FasL with Fas).