Abstract
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.
Highlights
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)
We have previously demonstrated in this model that chemotherapy exerts adjuvant effect to enhance the immunogenicity of the TME, permitting the generation of antitumor immune responses by subsequent intratumoral administration of HPV16-E7 long peptide without the need of additional adjuvant[9]
All TC-1 tumor-bearing mice treated with cisplatin, E7 long peptide, and Annexin A5 (AnxA5) survived at least 70 days after tumor challenge, while 60% of mice in the cisplatin and E7 long peptide group died by day 50 after tumor challenge, and all mice in remaining treatment groups died by day 40 after tumor challenge (Fig. 1c)
Summary
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). While we and others have previously demonstrated that many anti-cancer drugs, such as chemotherapy, possess immunostimulating effects and enhance the immunogenicity and efficacy of anti-cancer immunotherapy[7,8,9,10], chemotherapy-induced elevation of exposed-PS may in turn contribute to the formation of an immunosuppressive TME, thereby restricting the functions of tumor-targeting immune cells and preventing the immune clearance of tumors[11,12,13]. Due to the contribution of PS to immunosuppressive TME, AnxA5 may serve as a potential immune checkpoint inhibitor to enhance the immunogenicity of tumor-antigen specific immunotherapies, following the administration of cytotoxic chemotherapeutics[5,24]. We show that administration of AnxA5 alleviates the immunosuppressive properties of TME generated by chemotherapy and enhances the immunogenicity and antitumor efficacy of tumor antigen-specific immunization. Our data support the use of AnxA5 following chemotherapy as a promising immune checkpoint inhibitor for cancer treatment
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