Structural immunology of humoral and cellular recognition of a MUC1 breast cancer antigen

Abstract

MUC1 mucins have recently been the target of breast cancer vaccine trials. MUC1 peptide vaccine studies in mice have resulted in rejection of solid tumor and protection from further tumor challenge. These results represent the desired immune response in humans, but clinical trials have not shown MUC1 peptide-based vaccines to be effective. Clinical trials using tumor-associated MUC1 carbohydrate vaccines have produced immune responses with limited efficacy, and leave much room for improvement.Both immunological and biophysical evidence suggests that a combination of MUC1 peptide and carbohydrate moieties in a glycopeptide vaccine could be more effective at inducing an effective anti-tumor immune response in humans. The results presented in this thesis describe intermolecular interactions of MUC1 peptides and glycopeptides with the tumor-associated antibody B27.29. The identification of both peptide and carbohydrate interactions with B27.29 points to a mechanism for immune recognition of the tumor-associated MUC1 mucin, and suggests that a MUC1 glycopeptide vaccine might better represent the tumor-associated antigen. Further experiments are presented that give methodology for determining how MUC1 peptides or glycopeptides might stimulate a cellular immune response, as well. These results are discussed within the framework of developing a next-generation MUC1 glycopeptide vaccine that might be able to effectively treat and/or prevent recurrence of breast cancer.