Enhancing Tumor Immunogenicity through Hyaluronic Acid-Mediated Delivery of Nonself Antigenic Peptides

Tumor-specific cytotoxic T cells (CTLs) recognize and eliminate tumor cells presenting the tumor-associated antigens on major histocompatibility complex (MHC) class I molecules. However, the efficacy of vaccine-induced CTLs is often limited by the low immunogenicity of self-derived tumor antigens. Because the magnitude of an immune response is closely associated with antigen immunogenicity, strategies that enhance the antigenicity of tumor cells can improve the effectiveness of cancer vaccines. In this study, we prepared a series of conjugates consisting of hyaluronic acid (HA), a tumor-targeting carrier, and the highly immunogenic ovalbumin (OVA)-derived peptide OVA257–264. The peptide was conjugated to amino-modified HA through a disulfide linkage using a cysteine-extended OVA257–264 (C-OVA257–264). We then evaluated whether delivery of C-OVA257–264 could induce presentation of a foreign antigen on MHC class I molecules of B16F10 melanoma cells. Treatment of B16F10 cells with the conjugate HA-C-OVA257–264 efficiently induced presentation of C-OVA257–264 on H-2Kb molecules. Coculture of B16F10 cells treated with HA-C-OVA257–264 and splenocytes containing OVA257–264-specific CTLs resulted in robust interferon gamma production and pronounced CTL-mediated cytotoxicity. Similar antigen results were obtained using C-SARS902–909, a peptide capable of binding H-2Kb and potentially compatible with selected human HLA class I molecules. These findings indicate that foreign antigenic peptides delivered by HA can be presented on MHC class I molecules of tumor cells and subsequently recognized by antigen-specific CTLs. This antigen-replacement strategy represents a promising platform for the development of next-generation cancer vaccines and other antigen-specific immunotherapies.