IMMU-01. Microglia derived extracellular vesicles in the crosstalk between glioblastoma and infiltrating immune cells

Abstract Glioblastoma (GBM) is the most common and aggressive primary tumor of the central nervous system. GBM is characterized by a highly heterogenous and immune suppressive environment, in which almost 40% of the total tumor mass in composed by myeloid cells. In early stages of gliomagenesis, microglia (the resident macrophages of the brain) are the prevalent immune cells in the tumor, while in later stages they are replaced by bone marrow derived myeloid cells (macrophages and neutrophiles). Although it is now clear that the number of immune suppressive macrophages correlates with worst in GBM, the mechanisms by which they infiltrate the tumor are still unknown. Our data show that extracellular vesicles (EVs) produced by tumor associated microglia (TAMi) play a key role in the recruitment of immune cells from the periphery. We isolated EVs from 2 complementary models of TAMi (primary microglia and microglia cell line activated with tumor supernatant) and demonstrated that TAMi-EVs have the ability to cross the blood brain barrier and induce the activation and the expansion of highly motile inflammatory monocytes, in the bone marrow. Once activated, motile monocytes leave the bone marrow and infiltrate the tumor, where they differentiate toward pro-tumorigenic macrophages. Mechanistically, we showed that TAMi-EVs are specifically internalized by monocyte progenitor, and they induce their activation through IL1α. Our data show, for the first time, that EVs produced by microglia in the context of glioblastoma, are crucial for the cross-talk between the brain and the periphery, therefore playing a key role in the generation of an immune suppressive phenotype. A deep understanding of the role of EVs in the microglia-glioma cross-talk will unravel new pathways involved in gliomagenesis and open the possibility to the discover of new therapeutic targets.