Allogeneic tumor cell-derived extracellular vesicles stimulate CD8 T cell response in colorectal cancer

Most colorectal cancer (CRC) patients present with a microsat-ellite-stable phenotype, rendering them resistant to immune checkpoint inhibitors (ICIs). Among the contributors to ICI resistance, tumor-derived extracellular vesicles (TEVs) have emerged as critical players. Previously we demonstrated that autologous transfer of TEVs without miR-424 can induce tu-mor antigen-specific immune responses in CRC models. There-fore, we postulated that allogeneic TEVs, modified to lack miR-424 and derived from an MC38 cells, could induce CD8+ T cell responses while restraining CT26 cell-based tumor. Here, we show that prophylactic administration of MC38 TEVs, without miR-424, showed a significant augmentation in CD8+ T-cells within CT26 tumors. This allogenic TEV effect was evident in CT26 tumors but not B16-F10 melanoma. Furthermore, we demonstrated the capacity of dendritic cells (DCs) to inter-nalize TEVs, a possible mechanism to elicit immune response. Our investigation of autologously administered DCs, which had been exposed to modified TEVs, underscores their poten-tial to dampen tumor growth while elevating CD8+ T cell levels vis-a-vis MC38 wild-type TEVs exposed to DCs. Notably, the modified TEVs were well tolerated and did not increase periph-eral blood cytokine levels. Our findings underscore the poten-tial of modified allogeneic TEVs without immune-suppressive factors to elicit robust T cell responses and limit tumor growth.