title: Enhanced major histocompatibility complex class I binding and immune responses through anchor modification of the non-canonical tumour-associated mucin 1-8 peptide.
abstract: Designing peptide-based vaccines for therapeutic applications in cancer immunotherapy requires detailed knowledge of the interactions between the antigenic peptide and major histocompatibility complex (MHC) in addition to that between the peptide-MHC complex and the T-cell receptor. Past efforts to immunize with high-affinity tumour-associated antigenic peptides have not been very immunogenic, which may be attributed to the lack of T cells to these peptides, having been deleted during thymic development. For this reason, low-to-medium affinity non-canonical peptides represent more suitable candidates. However, in addition to the difficulty in identifying such antigens, peptide binding to MHC, and hence its ability to induce a strong immune response, is limited. Therefore, to enhance binding to MHC and improve immune responses, anchor modifications of non-canonical tumour-associated peptides would be advantageous. In this study, the non-canonical tumour-associated peptide from MUC1, MUC1-8 (SAPDTRPA), was modified at the MHC anchor residues to SAPDFRPL (MUC1-8-5F8L) and showed enhanced binding to H-2Kb and improved immune responses. Furthermore, the crystal structure of MUC1-8-5F8L in complex with H-2Kb was determined and it revealed that binding of the peptide to MHC is similar to that of the canonical peptide OVA8 (SIINFEKL).
authors.affiliation: Burnet Institute at Austin, Immunology and Vaccine Laboratory, Heidelberg, VIC, Australia. eliadalzoura@hotmail.com
authors.forename: Eliada
authors.initials: E
authors.lastname: Lazoura
authors.forename: Jodie
authors.initials: J
authors.lastname: Lodding
authors.forename: William
authors.initials: W
authors.lastname: Farrugia
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ramsland
authors.forename: James
authors.initials: J
authors.lastname: Stevens
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Pietersz
authors.forename: Vasso
authors.initials: V
authors.lastname: Apostolopoulos
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000737:chemistry / Q000276:immunology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D004331:Drosophila melanogaster; D006183:H-2 Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D007111:Immunity, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D010446:Peptide Fragments