Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands

Abstract

Autocrine and paracrine cell communication can be conveyed by multiple mediators, including membrane-associate proteins, secreted proteins and exosomes. Exosomes are 30–100 nm endosome-derived vesicles consisting in cytosolic material surrounded by a lipid bilayer containing transmembrane proteins. We have previously shown that dendritic cells (DCs) express on their surface multiple TNF superfamily ligands (TNFSFLs), by which they can induce the apoptotic demise of tumor cells as well as the activation of natural killer (NK) cells. In the present study, we demonstrate that, similar to DCs, DC-derived exosomes (DCex) express on their surface TNF, FasL and TRAIL, by which they can trigger caspase activation and apoptosis in tumor cells. We also show that DCex activate NK cells and stimulate them to secrete interferonγ (IFNγ) upon the interaction of DCex TNF with NK-cell TNF receptors. These data demonstrate that DCex can mediate essential innate immune functions that were previously ascribed to DCs.

Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway

“…We found an elevated expression of TNF‐α in mature DC‐exos and they were mainly expressed on exosomal membrane. This finding was consistent with previous studies 8, 24. We then down‐regulated TNF‐α in DC‐exos and observed that the expression of adhesion molecules by HUVECs were attenuated, indicating a direct interaction between DC‐exos and HUVECs by TNF‐α.…”

“…If a protein is mainly located on the membrane, then the intact concentration should be as similar as the lysed concentration. Otherwise, the lysed concentration should be significantly higher than the intact concentration 8. Using this method, we found that TNF‐α was mainly expressed on the exosomal membrane and mature DC‐exos, compared with immature DC‐exos, displayed a higher expression of TNF‐α (Fig.…”

“…Upon being released from cells, exosomes can distribute in biological fluids and be up‐taken by the same or a different type of cells, which then interact with exosomes and present biological functions 6. Previous studies showed that DC‐derived exosomes (DC‐exos) can exert biological effects via membrane proteins or inner contained miRNAs 7, 8, 9. Here, in the present study, we aimed at investigating whether DC‐exos are involved in endothelial inflammation and atherosclerosis.…”

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

“…To test the potential for exosomes to be used as cell-free vaccines against cancers, DC-derived exosomes have undergone phase I trial and are currently in phase II trial [12,103–105]. In addition to MHC-bound antigens expressed on the exosomal surface, mature DC-derived exosomes also show surface expression of ICAM-1, which is important for the induction of immune responses, such as T-cell activation [106], and the NKG2D ligand, which is a TNF superfamily ligand that binds directly to NK cells to induce their activation/proliferation and cause an anti-tumour immune response [107,108]. …”

Therapeutic and diagnostic applications of extracellular vesicles

“…miRNA, mRNA), integrins (type of integrin can be cell-type specific), lysobisphosphatidic acid (LBPA), cholesterol, ganglioside GM3 [29,30]. Cell type specific: MHC-II, CD80, CD86 and complement shielding proteins CD55/59 (in DC) [31], tumor-associated antigens (TAA; e.g. GP100 in melanoma cells) [32], perforin (in natural killer T cells) [33].…”