Epithelial cell mucin (MUC1) expressed on breast, pancreatic, colon, and other adenocarcinomas, was the first human tumor antigen to be reported as a CTL target and thus the first example that human tumors elicit T cell immunity. MUC1 is expressed on all epithelial adenocarcinomas and on multiple myelomas. Together they comprise over 83 percent of all human tumors. Complete understanding of MUC 1 as an immunogen or a target of immunotherapy could translate into novel and effective approaches for preventing or managing a very large majority of human tumors. The emphasis until now has been strictly on peptide epitopes and primarily on CTL responses. MUC1 is a heavily glycosylated protein, however, whose processing by APC is very important but poorly understood, not unlike processing of other glycoproteins. The hypothesis we will be testing is that processing of MUC1 glycoprotein can be manipulated to generate both peptide and glycopeptide epitopes to stimulate peptide and glycopeptide specific T cells. This complex repertoire that can be generated through vaccination can prevent MUC1 tumor growth but some or all of its components may also cause autoimmunity. In Specific Aim I, we will try to understand the rules governing uptake and processing of MUC1, a glycoprotein antigen, by professional antigen presenting cells (APC) and define the nature of processed epitopes presented to T cells. In Specific Aim II, we will determine the contribution of MUC1-specific responses against peptide epitopes and glycopeptide epitopes to tumor rejection, and if these responses are tumor specific or could potentially be autoimmune. In Specific Aim III, we will test immunogenicity, tumor rejection potential, tumor prevention potential and safety of MUC1 peptide and glycopeptide vaccines in mice that develop spontaneous MUC1+ pancreatic tumors. The goals of our new aims are to elicit most comprehensive and effective anti-MUC1 immune responses possible, to test their individual autoimmune potential and if found, to define solutions that will allow safe use of MUC1 for prevention and control of human tumors. These answers are very important to obtain at this point in time. Phase I/Il clinical trials are ongoing around the world testing MUC1 vaccines in cancer patients. They are not predictive of what will happen if and when strong immune responses are generated in healthier patients earlier in the disease. This can now be examined in relevant animal models, MUC1 and HLA transgenic mice that develop spontaneous MUC1 + tumors.
NIH ExPorter
NIH ExPorter