Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells

Glioblastoma multiforme (GBM) is the most common primary brain tumor and is without exception lethal. GBMs modify the immune system, which contributes to the aggressive nature of the disease. Particularly, cells of the monocytic lineage, including monocytes, macrophages and microglia, are affected. We investigated the influence of GBM-derived extracellular vesicles (EVs) on the phenotype of monocytic cells. Proteomic profiling showed GBM EVs to be enriched with proteins functioning in extracellular matrix interaction and leukocyte migration. GBM EVs appeared to skew the differentiation of peripheral blood-derived monocytes to alternatively activated/M2-type macrophages. This was observed for EVs from an established cell line, as well as for EVs from primary cultures of GBM stem-like cells (GSCs). Unlike EVs of non-GBM origin, GBM EVs induced modified expression of cell surface proteins, modified cytokine secretion (e.g., an increase in vascular endothelial growth factor and IL-6) and increased phagocytic capacity of the macrophages. Most pronounced effects were observed upon incubation with EVs from mesenchymal GSCs. GSC EVs also affected primary human microglia, resulting in increased expression of Membrane type 1-matrix metalloproteinase, a marker for GBM microglia and functioning as tumor-supportive factor. In conclusion, GBM-derived EVs can modify cells of the monocytic lineage, which acquire characteristics that resemble the tumor-supportive phenotypes observed in patients. What's New? The prognosis of patients with glioblastoma multiforme (GBM) remains dismal. GBM tumors can modify the immune response, both locally and systemically, which contributes to the aggressive nature of the disease. In this study, the authors found that GBM-derived extracellular vesicles (EVs) were able to modify the phenotypes of immune cells such as microglia and blood-derived monocytes in ways that made them more tumor-supportive. Changes included altered cytokine secretion by macrophages and increased expression of Membrane type 1-matrix metalloproteinase (MT1-MMP) by microglia. These results suggest that blocking GBM-derived EVs may have therapeutic potential.