Dendritic Cell Derived‐Extracellular Vesicles Engineered to Express Interleukin‐12 and Anti‐CTLA‐4 on Their Surface for Combinational Cancer Immunotherapy

Abstract

ABSTRACT Dendritic cell (DC)‐derived extracellular vesicles (DEVs) are promising candidates for cancer vaccines, but their therapeutic effects still need further optimization. In this study, we utilized neoantigens, lipopolysaccharide and IFN‐γ to induce the maturation of DCs, and then isolated DEVs derived from these mature DCs. We showed that the immune checkpoint inhibitor (anti‐CTLA‐4 antibody, aCTLA‐4) can improve the immunostimulatory function of DEVs by directly activating T cells through immune checkpoint signal blockade. The cytokine interleukin‐12 (IL‐12), as one of the third signals for T cell activation, can also enhance the capability of DEVs to activate T cells directly. Based on these findings, we designed the engineered DEVs conjugated with IL‐12 and aCTLA‐4 (DEV@IL‐12‐aCTLA‐4) to improve the therapeutic potential of DEVs by providing sufficient immune regulatory signals. Moreover, the carrier property of DEVs also contributes to the delivery of IL‐12 and aCTLA‐4 to lymph nodes. This indicates that the conjugation of DEVs with IL‐12 and aCTLA‐4 constitutes a complementary approach, where IL‐12 and aCTLA‐4 help to enhance the T cell activation effect of DEVs, and DEVs facilitate the delivery of IL‐12 and aCTLA‐4. Our results showed that DEV@IL‐12‐aCTLA‐4 can enhance the Th1 immune response and reverse exhausted CD8+ T cells in the tumour microenvironment, effectively inducing robust T cell immune responses and inhibiting tumour growth in tumour‐bearing mice. Overall, this study expands the theoretical foundation of DEVs and provides a universal strategy for optimizing cancer combination immunotherapy by reprogramming DEVs.