Inhibition of lipid raft-mediated endocytosis prevents the induction of MDSCs by glioblastoma extracellular vesicles.

Extracellular vesicles (EVs) are small lipid bilayer structures released from different cell types and contain bioactive molecules including nucleic acids and proteins that shape the tumor microenvironment through cell-cell interaction. Tumor-derived EVs have been demonstrated to play a critical role in promoting an immunosuppressive landscape that ultimately contributes to immune escape. In glioblastoma, we found that tumor-derived EVs induced the expansion of myeloid-derived suppressor cells (MDSCs), which impair T cell proliferation in vitro. The mechanisms of EV uptake including lipid-raft mediated endocytosis have been well described. These cholesterol rich microdomains on cellular membranes act as a docking mechanism for EV uptake. Co-culturing of GBM-derived EVs with donor monocytes in the presence of Methylβ-cyclodextrin, a cholesterol depleting reagent, resulted in impaired EV uptake by monocytes, reversal of MDSC induction, and rescue of T cell proliferation in a dose-dependent manner. These results serve as a possible avenue for finding treatment adjuncts along with immune checkpoint inhibitors to combat the immunosuppressive milieu in glioblastoma.