Abstract
Tumor-derived extracellular vesicles (TEVs) play crucial roles in mediating immune responses, as they carry and present functional MHC-peptide complexes that enable them to modulate antigen-specific CD8+ T-cell responses. However, the therapeutic potential and immunogenicity of TEV-based therapies against bladder cancer (BC) have not yet been tested. Here, we demonstrated that priming with immunogenic Extracellular Vesicles (EVs) derived from murine MB49 BC cells was sufficient to prevent MB49 tumor growth in mice. Importantly, antibody-mediated CD8+ T-cell depletion diminished the protective effect of MB49 EVs, suggesting that MB49 EVs elicit cytotoxic CD8+ T-cell-mediated protection against MB49 tumor growth. Such antitumor activity may be augmented by TEV-enhanced immune cell infiltration into the tumors. Interestingly, MB49 EV priming was unable to completely prevent, but significantly delayed, unrelated syngeneic murine colon MC-38 tumor growth. Cytokine array analyses revealed that MB49 EVs were enriched with pro-inflammatory factors that might contribute to increasing tumor-infiltrating immune cells in EV-primed MC-38 tumors. These results support the potential application of TEVs in personalized medicine, and open new avenues for the development of adjuvant therapies based on patient-derived EVs aimed at preventing disease progression.
Highlights
Extracellular vesicles (EVs) are small round double-membrane-enclosed vesicles secreted by most cell types that can transport a wide variety of cargos including proteins, nucleic acids and lipids [1]
In summary, we found that MB49 EVs, in addition to enhancing CD8+ T-cell-mediated antituEmVosrairme mreulenaeseredspdounrsinesg(nFoigrumraesl c2e–l4lu),lcaarnaactlsivoitbyoobsyt immomstucneellsytyspteems, ainctcilvuadtiionng aimt ammourneegaenndertaulmleovrelcaenllds, parnodmcoatne omveedriaaltleimcemllu–cneellscuormvemilluanniccea.tion resulting in changes in
EVs are released during normal cellular activity by most cell types, including immune and tumor cells, and can mediate cell–cell communication resulting in changes in the behavior of recipient cells
Summary
Extracellular vesicles (EVs) are small round double-membrane-enclosed vesicles secreted by most cell types that can transport a wide variety of cargos including proteins, nucleic acids and lipids [1]. While initially disregarded as a form of cellular garbage, in the late 1990s, it was discovered that EVs could play a variety of functional roles in the physiology and pathophysiology of different diseases, including cardiovascular diseases, diabetes and cancer. 25–30% of BC patients exhibit muscle-invasive (MI) disease, and 50% of these MIBC patients will develop metastatic disease, which is associated with poor 5-year survival rates [15]. High tumor recurrence rates and the high morbidity in NMI BC and mortality associated with MI BC make BC one of the most expensive cancers to treat and manage, with the highest lifetime treatment cost per patient owing to the need for constant clinical visits to monitor for potential future tumor development [16–18]. Better therapeutic options for BC patients are needed, such as patient-specific therapies capable of reducing the high tumor recurrence
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