Immunology of O-Glycosylated Proteins: Approaches to the Design of a MUC1 Glycopeptide-Based Tumor Vaccine
Franz-Georg Hanisch and Tanja Ninkovic
Affiliation: Institute of Biochemistry II, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Koln, Germany.
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 carbohydratepeptide 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 Oglycosylated 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.
Keywords: MUC1, O-glycosylation, glycopeptides, processing, MHC presentation, glycopeptide-specific T cells, tumor vaccine
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