| MUC1 is a tumor-associated antigen that is overexpressed and aberrantly glycosylated in malignantly transformed ductal epithelial tissues, resulting in the exposure of normally cryptic epitopes of the core protein to cells of the immune system. Preclinical and clinical studies have focused on utilizing peptide vaccine formulations derived from regions within the tandem repeat, while little is known whether regions outside the tandem repeat are immunogenic, and if so, whether they can be used as targets for vaccine therapies. In addition, cellular and molecular requirements for immunity directed against MUC1-expressing tumors derived from different organ sites is not well understood. These problems were addressed in vivo by challenging wildtype mice and mice genetically deficient in molecules related to immunity with MUC1-expressing murine tumors derived from the skin or pancreas.; In the first set of studies described in this dissertation, we produced a soluble form of MUC1 vaccine that consisted of regions flanking the tandem repeat, using the bacterial GST expression system, and identified limitations in utilizing this type of expression system to produce recombinant proteins for immunization purposes. In the second set of studies, we examined the prophylactic and therapeutic efficacy of a MUC1 peptide derived from the juxtamembrane domain conjugated to a conformationally biased peptide agonist of human C5a anaphylatoxin to protect mice from MUC1-expressing tumors and determined that high serum antibody levels directed against the immunizing peptide may be associated with a poor prognosis for survival. In a third set of experiments, we identified cellular and molecular immune components that played critical and nonredundant roles in immunity directed against a MUC1-expressing murine pancreatic carcinoma: CD8+ T cells expressing TCRα/β, NK cells/monocytes, CD28 and CD40:CD40L costimulation, IFN-γ, LT-α, perforin, and FasL. In our last set of experiments, we examined the role of B cells in tumor immunity by using a B cell-deficient mouse strain (μMT) and demonstrated enhanced, non-antigen-specific immune responses to tumors in these animals. |
