Targeting cryptic epitope with modified antigen coupled to the surface of liposomes induces strong antitumor CD8 T-cell immune responses invivo.

Abstract

Active cancer immunotherapy, such as cancer vaccine, is based on the fundamental knowledge that tumor-associated antigens (TAAs) are presented on MHC molecules for recognition by specific T cells. However, most TAAs are self-antigens and are also expressed on normal tissues, including the thymus. This fact raises the issue of the tolerance of the TAA-specific T-cell repertoire and consequently the inability to trigger a strong and efficient antitumor immune response. In the present study, we used antigens chemically coupled to the surface of liposomes to target telomerase reverse transcriptase (TERT), a widely expressed self/tumor antigen. Taking advantage of the high homology between mouse and human TERT, we investigated immunogenicity and antitumor efficiency of the liposomal TERT peptides in HLA-A*0201 transgenic HHD mice. Using the heteroclitical peptide-modifying approach with antigen-coupled liposomes, we identified a novel cryptic epitope with low affinity for HLA*0201 molecules derived from TERT. The heteroclitical variant derived from this novel low affinity peptide exhibited strong affinity for HLA*0201 molecules. However, it induced only weak CD8 T-cell immune responses in HHD mice when emulsified in IFA. By contrast, when coupled to the surface of the liposomes, it induced powerful CD8 T-cell immune responses which cross-reacted against the original cryptic epitope. The induced CD8 T cells also recognized endogenously TERT-expressing tumor cells and inhibited their growth in HHD mice. These data suggest that heteroclitical antigen derived from low affinity epitope of tumor antigens coupled to the surface of liposome may have a role as an effective cancer vaccine candidate.