Dendritic cell-derived exosomes need to activate both T and B cells to induce antitumor immunity.

Exosomes are secreted membrane nanovesicles of endosomal origin and are considered potential cancer vaccine vectors. Phase I clinical trials have been successfully conducted with tumor peptide-loaded exosomes derived from dendritic cells (dexosomes), and a phase II clinical trial is ongoing. However, much is still unknown regarding the in vivo role of dexosomes and whether their immunogenicity can be enhanced. We previously reported that dexosomes induce CD4(+) T cell responses in a B cell-dependent manner, suggesting that immunization with dexosomes carrying only T cell peptides induce suboptimal immune responses. In this study, we show that CD8(+) T cell responses were induced in vivo when mice were immunized with protein-loaded, but not peptide-loaded, dexosomes. We also show that the cytotoxic T cell response was totally dependent on CD4(+) T cells and, interestingly, also on B cells. Mice deficient in complement activation and Ag shuttling by B cells have lower responses to protein-loaded dexosomes, showing involvement of these B cell-mediated mechanisms. Finally, protein-loaded dexosomes were superior in protecting against tumor growth. In conclusion, proper activation of CD4(+) T and B cells needs to be considered when designing cancer vaccines to ensure full potential of the treatment.

Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic disease of unknown aetiology characterised by granuloma formation and the presence of interferon γ (IFNγ)-producing T cells that cause inflammation and tissue damage in multiple organs, especially the lung. Exosomes are nano-sized immunomodulatory vesicles of endosomal origin released from a diverse range of cells and are also found in physiological fluids including bronchoalveolar lavage fluid (BALF) from healthy individuals. OBJECTIVE: To investigate whether exosomes are enriched in the lungs of patients with sarcoidosis compared with healthy individuals and whether they could contribute to pathogenesis. DESIGN: BALF exosomes from patients with sarcoidosis (n=36) and healthy controls (n=14) were compared by electron microscopy, flow cytometry, western blot analysis and mass spectrometry. BALF exosomes were incubated with autologous peripheral blood mononuclear cells (PBMCs) or the human bronchial epithelial cell line 16HBE14o-. Cytokines were measured by ELISPOT and ELISA. RESULTS: BALF from patients with sarcoidosis showed increased levels of exosomes compared with healthy individuals. Exosomes from patients showed significantly higher expression of MHC class I and II, tetraspanins CD9, CD63 and CD81 as well as neuregulin-1, known to be associated with cancer progression. Furthermore, BALF exosomes from patients induced significantly higher IFNγ and interleukin (IL)-13 production in autologous PBMCs compared with healthy individuals and could also stimulate IL-8 production from epithelial cells. CONCLUSION: The results indicate for the first time a role for exosomes in human lung disease with possible contributions to the initiation and progression of inflammation in sarcoidosis. This suggests that exosomes may be a new potential target for the clinical treatment of lung diseases.