Extracellular vesicles and co-isolated endogenous retroviruses differently affect dendritic cells

Federico Cocozza, Lorena Martin-Jaular, Lien Lippens, Aurelie Di Cicco, Yago A Arribas, Florent Dingli, Michael Richard, Louise Merle, Patrick Poullet, Damarys Loew, Daniel Lévy, An Hendrix, George Kassiotis, Alain Joliot, Mercedes Tkach, Clotilde Théry

ABSTRACTCells secrete membrane-enclosed extracellular vesicles (EVs) and non-vesicular nanoparticles (ENPs) that may play a role in intercellular communication. Tumor-derived EVs have been proposed either to induce immune priming of antigen presenting cells, or, to be immuno-suppressive agents promoting tumor immune escape. We suspect that such disparate functions are due to variable composition in EV subtypes and ENPs of the analyzed EV preparations. We aimed to exhaustively characterize the array of secreted EVs and ENPs of murine tumor cell lines. Unexpectedly, we identified virus-like particles (VLPs) from endogenous murine leukemia virus in preparations of EVs produced by tumor cells. We established a robust protocol to separate small (s)EVs from VLPs and ENPs. We compared their protein composition and analyzed their functional interaction with target dendritic cells (DCs). ENPs were poorly captured and did not affect DCs. sEVs specifically induced DC death. A mixed EV/VLP preparation was the most efficient to induce DC maturation and antigen presentation. Our results call for systematic re-evaluation of the respective proportions and functions of non-viral EVs and VLPs produced by tumors and their contribution to anti-tumor immune responses and to tumor progression.