Enhanced major histocompatibility complex class I binding and immune responses through anchor modification of the non‐canonical tumour‐associated mucin 1‐8 peptide

• Published in: Immunology Vol. 119; no. 3; pp. 306 - 316
• Main Authors: Lazoura, Eliada, Lodding, Jodie, Farrugia, William, Ramsland, Paul A., Stevens, James, Wilson, Ian A., Pietersz, Geoffrey A., Apostolopoulos, Vasso
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2006; Wiley Subscription Services, Inc; Blackwell Science Inc
• Subjects: anchor modifications; Animals; Antigens, Neoplasm - immunology; Cancer Vaccines - chemistry; Cancer Vaccines - immunology; Cell Line; Crystallography, X-Ray; Drosophila melanogaster; H-2 Antigens - metabolism; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; H‐2Kb; Immunity, Cellular; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Molecular; mucin 1; mucin 1‐8; Mucin-1 - genetics; Mucin-1 - immunology; Mucin-1 - metabolism; Mutation; non‐canonical peptide; Original; Peptide Fragments - genetics; Peptide Fragments - immunology; Peptide Fragments - metabolism; Protein Binding; Structure-Activity Relationship; T-Lymphocyte Subsets - immunology; vaccine design
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/j.1365-2567.2006.02434.x

Summary
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).