Exosome transportation-mediated immunosuppression relief through cascade amplification for enhanced apoptotic body...

Cancer vaccines represent the most promising strategies in the battle against cancers. Eliciting a robust therapeutic effect with vaccines, however, remains a challenge owing to the weak immunogenicity of autologous tumor antigens and highly immunosuppressive microenvironment. In the present study, we constructed CpG oligodeoxyribonucleotide (CpG ODN)-loaded cancer cell apoptotic bodies (Abs) as cancer vaccines for enhanced immunotherapy through cascade amplification-mediated immunosuppression relief. Abs that contain an abundant source of tumor-specific neoantigens and other tumor-associated antigens (TAAs) can be regarded as vaccines with higher immunogenicity. The de novo synthesized Abs-CpG could target and polarize macrophages to improve the immunosuppressive microenvironment. More importantly, we found that the effect of immunosuppression relief was cascade amplified, which was mediated by M1 macrophage-derived exosome transportation. Our results showed that CpG ODN polarized macrophages to M1 type and produced a large amount of TNF-α, which then activated cell division control protein 42 (Cdc42). Interestingly, we found that exosomes from M1 macrophages delivered Cdc42 and CpG to adjacent macrophages and further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by Abs-CpG with macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved, which then enhanced the performance of cancer vaccine therapy. Thus, we propose that a strategy of combining the Abs-based vaccine platform with the immunomodulatory approach represents the next generation of cancer immunotherapy. STATEMENT OF SIGNIFICANCE: 1. We discovered a relieving strategy for tumor immunosuppressive microenvironment: Abs-CpG polarized macrophages to M1 type, and M1 macrophage-derived exosomes delivered Cdc42 and CpG to adjacent macrophages, which then further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by the transfer of macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved. 2. As a vaccine, Abs contained both tumor-specific neoantigens and other tumor-associated antigens with higher immunogenicity and high clinical transformability.