title: Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine.
abstract: The mucin MUC1 is typically aberrantly glycosylated by epithelial cancer cells manifested by truncated O-linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and are susceptible to recognition by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Efforts to elicit CTLs and IgG antibodies against cancer-expressed MUC1 have not been successful when nonglycosylated MUC1 sequences were used for vaccination, probably due to conformational dissimilarities. Immunizations with densely glycosylated MUC1 peptides have also been ineffective due to impaired susceptibility to antigen processing. Given the challenges to immuno-target tumor-associated MUC1, we have identified the minimum requirements to consistently induce CTLs and ADCC-mediating antibodies specific for the tumor form of MUC1 resulting in a therapeutic response in a mouse model of mammary cancer. The vaccine is composed of the immunoadjuvant Pam(3)CysSK(4), a peptide T(helper) epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three components was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs which recognized only nonglycosylated peptide. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control. As a result, immunization with the glycosylated tripartite vaccine was superior in tumor prevention. Besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.
authors.affiliation: Department of Biochemistry, Mayo Clinic College of Medicine and Mayo Clinic Comprehensive Cancer Center, Scottsdale, AZ 85259, USA.
authors.forename: Vani
authors.initials: V
authors.lastname: Lakshminarayanan
authors.forename: Pamela
authors.initials: P
authors.lastname: Thompson
authors.forename: Margreet A
authors.initials: MA
authors.lastname: Wolfert
authors.forename: Therese
authors.initials: T
authors.lastname: Buskas
authors.forename: Judy M
authors.initials: JM
authors.lastname: Bradley
authors.forename: Latha B
authors.initials: LB
authors.lastname: Pathangey
authors.forename: Cathy S
authors.initials: CS
authors.lastname: Madsen
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Boons
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D019496:Cancer Vaccines / Q000737:chemistry / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D006031:Glycosylation; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D008324:Mammary Tumor Virus, Mouse / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D047368:Tumor Burden / Q000276:immunology; D014614:Vaccines, Synthetic / Q000737:chemistry / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D018396:Mucin-1; D014614:Vaccines, Synthetic