Kang and Park et al. treated tumor-bearing mice with cisplatin, tumor-specific-antigen peptides (intratumorally), and Annexin A5 (Anx, a phosphatidylserine ligand). The treatment reversed cisplatin-induced Treg, MDSC, TGFβ, and PD-L1 immunosuppression, and enhanced tumor control and tumor-infiltrating (TI) CD4+ and antigen-specific CD8+ T cells, M1 macrophages, and TNFα levels. Systemic delivery of antigen as a tumor-homing Anx/tumor-antigen fusion protein instead of intratumoral peptides further boosted tumor control as well as systemic and TI tumor-specific immune responses, and synergized with other checkpoint inhibitors.
Contributed by Paula Hochman
The interaction between immune cells and phosphatidylserine (PS) molecules exposed on the surface of apoptotic-tumor bodies, such as those induced by chemotherapies, contributes to the formation of an immunosuppressive tumor microenvironment (TME). Annexin A5 (AnxA5) binds with high affinity to PS externalized by apoptotic cells, thereby hindering their interaction with immune cells. Here, we show that AnxA5 administration rescue the immunosuppressive state of the TME induced by chemotherapy. Due to the preferential homing of AnxA5 to the TME enriched with PS+ tumor cells, we demonstrate in vivo that fusing tumor-antigen peptide to AnxA5 significantly enhances its immunogenicity and antitumor efficacy when administered after chemotherapy. Also, the therapeutic antitumor effect of an AnxA5-peptide fusion can be further enhanced by administration of other immune checkpoint inhibitors. Our findings support the administration of AnxA5 following chemotherapy as a promising immune checkpoint inhibitor for cancer treatment.