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

Abstract

Cells 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.

Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy

“…Our updated knowledge of role of DCs in cancer immunology indicates that the interactions between DCs and T cell do not only govern T cell priming in the lymph nodes (LNs), but also are critical throughout the cancer immunity cycle including key reactions within the TME that promote antitumor effector responses [ 208 , 209 ]. While the ability of DCs to present antigens as well as their maturation could be impaired by tumor-derived exosomes via diverse of mechanisms which has been reviewed elsewhere [ 195 , 196 ], a recent study by Cocozza et al aroused us to re-evaluate the respective proportions and functions of tumor-derived exosomes due to their heterogeneity [ 210 ]. Myeloid-derived suppressor cells (MDSCs) are major components of the immune suppressive TME whose differentiation has been demonstrated to be regulated by exosomal miRNAs derived from cancer cells [ 211 – 214 ].…”

Stoichiometric constraints for detection of EV-borne biomarkers in blood

“…The virus-like particles from endogenous murine leukemia virus have also been identified in murine models and in preparations of EVs produced by tumor cells. The development of a purification method to separate viruses and EVs have allowed to distinguish their separate contribution to anti-tumor responses and tumor progression [27].…”

Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia

“…Extracellular vesicles (EVs) are membrane-enclosed vesicles secreted by cells into the extracellular environment, and are an important means of cell communication [1][2][3] .…”