Immunogenic Structural Features of a Breast Tumor-Specific Epitope for Cancer Immunotherapy.

The objectives of the research program are to study the structure-immunogenicity relationships of a hypoglycosylated human tumor-specific mucin common to breast and other adenocarcinomas. Hypoglycosylation of breast mucin leads to exposure of a tumor-specific epitope TSE. The structural and immunogenic properties of the TSE are being examined using synthetic mucin peptides and recombinant mucin proteins that contain the TSE andor mutations in potential glycosylation sites surrounding the TSE. A single 20 amino acid tandem repeat of mucin is immunogenic. It stimulates the production of polyclonal antibodies and tumor-specific cytotoxic T lymphocytes. The single tandem repeat peptide was shown to contain few elements of preferred conformation, based on 1H-NMR spectroscopy. A model of the distribution of the oligosaccharide side chains along the mucin core protein was developed showing that the carbohydrates may not surround the protein in a uniform coating. Thus, regions of the core protein are exposed under normal circumstances, yet tumor-specific epitopes remain masked by the sugars in the non-malignant cells. Further understanding of the structure-immunogenicity relationships of tumor-specific immunogens is essential for maximizing the use of synthetic peptide immunogens and tumor-specific cells as a potential adoptive immunotherapy for patients with cancer, and the development of a potential vaccine.