Targeted delivery of antigenic CTL peptide to tumor loci by Annexin V renders tumor cells susceptible to adaptive CD8+ cell immunity

Antigen-specific immunotherapy represents a promising methodology to control tumors because it can stimulate the immune system to specifically target and eliminate tumor cells. To overcome the challenge of immune tolerance, which is common to immunotherapy, we generated a novel chimeric protein to selectively coat tumor cells with a foreign immunogenic CD8+ T cell (CTL) peptide(s) recognized by preexisting immunity so that immune tolerance could be bypassed and preexisting immunity could control tumors. In the current study, we exploited the fact that tumor cells undergo significant apoptotic cell death following conventional cancer treatment, to generate various chimeric proteins containing annexin V (annV), which binds selectively to apoptotic cells, to target immunogenic CTL epitopes to tumor loci. We assessed the therapeutic effects of these chimeric proteins alone and in combination with cisplatin chemotherapy to enhance tumor cell apoptosis. We show that annV selectively delivers the therapeutic chimeric proteins to the apoptotic tumor loci and that treatment of tumorbearing mice with various chimeric ann V proteins could elicit potent antigen-specific CD8+ T cell-mediated immune responses and antitumor effects. Furthermore, these immune responses and antitumor effects were significantly improved when the chimeric proteins were administered in combination with the cisplatin. This strategy may serve as a platform technology for the development of antigen-specific cancer immunotherapies to bypass immune tolerance for the control of a wide range of cancers.

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