title: Immunology of O-glycosylated proteins: approaches to the design of a MUC1 glycopeptide-based tumor vaccine.
abstract: Until about 1990 there was general consent about the assumption that only protein and peptide antigens have the capacity of CD4(+) or CD8(+) T-cell stimulation. Since about ten years evidence is now accumulating that carbohydrate-peptide epitopes do play a role in classical MHC-mediated immune responses. This holds true for glycopeptides, where the glycan chain is short and not located at an "anchor residue" needed for MHC interaction. T-cell recognition of O-glycosylated peptides is potentially of high biomedical significance, because it can mediate the immune protection against microorganisms, the vaccination in anti-tumor therapies, but also some aspects of autoimmunity. The epithelial type 1 transmembrane mucin MUC1 is established as a marker for monitoring recurrence of breast cancer and is a promising target for immunotherapeutic strategies to treat cancer by active specific immunization. Natural human immune responses to the tumor-associated glycoforms of the mucin indicate that antibody reactivities are more directed to glycopeptide than to non-glycosylated peptide epitopes. To overcome the weak immunogenicity of the natural target, heavily O-glycosylated MUC1, the question was addressed whether O-linked glycans remain intact during processing in the MHC class II pathway and interfere with endosomal processing and peptide presentation. Attempts were made to define on a biochemical level the structural requirements for an efficient endosomal proteolysis catalyzed by cathepsin L in antigen-presenting cells. Evidence based on work with CD4(+) T-hybridomas confirms that O-glycopeptides can be effectively presented to T-cells and that glycans can form integral parts of the TCR defined epitopes. Similar approaches are currently followed in the MHC class I pathway which aim at the identification of immunogenic glycopeptides generated by immunoproteasomes.
authors.affiliation: Center of Biochemistry, Medical Faculty, and Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Köln, Germany. franz.hanisch@uni-koeln.de
authors.forename: Franz-Georg
authors.initials: FG
authors.lastname: Hanisch
authors.forename: Tanja
authors.initials: T
authors.lastname: Ninkovic
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019496:Cancer Vaccines / Q000737:chemistry / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D006020:Glycopeptides / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D008285:Major Histocompatibility Complex; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D015202:Protein Engineering / Q000379:methods*; D011506:Proteins / Q000737:chemistry*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes; D006020:Glycopeptides; D018396:Mucin-1; D010455:Peptides; D011506:Proteins