DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell–dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell–based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.
Jonathan M. Pitt, Fabrice André, Sebastian Amigorena, Jean-Charles Soria, Alexander Eggermont, Guido Kroemer, Laurence Zitvogel
Dex interactions with immune cells.
Dex may stimulate T cells by direct and indirect routes. The presence of MHC-I and MHC-II molecules on the surface of Dex gives them the potential to directly stimulate CTLs and CD4+ T cells, respectively. Dex surface costimulatory molecules aid this process. A more likely route for Dex stimulation of T cells occurs indirectly via bystander DCs through two possible mechanisms. The first involves Dex internalization and transfer of antigenic peptides to MHC molecules of the DC. These MHC/peptide complexes may then be transported to the DC surface for presentation to T cells. The second mechanism involves Dex transfer of MHC/peptide complexes directly to the DC surface, a process termed cross-dressing. It has been suggested that Dex may also transfer MHC/peptide complexes to tumor cell surfaces, enabling tumor cell targeting by host T cells. Additionally, Dex have been shown to possess BAG6, NKG2D-L, and the IL-15/IL-15Rα complex, which can each result in NK cell activation.