): The lack of clinically significant immune responses directed against either hematologic or solid tumors is striking. Failure to generate immunity to tumors may be due to the inability of the tumors to present tumor-specific antigens or active inhibition of such responses by soluble or cell surface molecules expressed by the tumors. Muc-1 is a cell surface molecule, expressed widely on glandular epithelium and known to be shed into the lumenal space in breast milk. It is overexpressed on the surface of adenocarcinomas and can be found circulating in the blood of cancer patients. Despite a large number of descriptive studies on this molecule, its function is not known. The investigators' laboratory recently showed that cell surface and soluble forms of Muc-1 induce apoptosis in activated CD4+ T cells. Moreover, Muc-1 must be coexpressed with MHC class II molecules in order for it to induce apoptosis. These data suggest an immunomodulatory function of Muc-1 that may be used by tumors that express it to suppress immune responses to them. They propose to investigate both the physiology and the pathophysiology of Muc-1. They have designed several approaches to isolate the counter receptor on T cells that mediates the Muc-1 death signal. Experiments will be performed that elucidate the role of class II molecules in Muc-l-mediated apoptosis. Specifically, the applicants will investigate the possibility that Muc-1 binds to class II heterodimers in a non-covalent fashion reminiscent of viral superantigens, but with opposite consequences for the T cell. They also plan to focus on the physiology of this molecule. Their working hypothesis is that Muc- 1 may be responsible for maintaining or establishing immune tolerance at an epithelial surface, especially after inflammation. The structure of Muc-1 derived peptides shows a novel secondary structure that forms a repeating """"""""knob"""""""" on the backbone of the molecule. These """"""""knobs"""""""" also form immunodominant epitope of the molecule. They will perform structure-function studies using Muc-1 derived peptides and site directed mutagenesis of the molecule to determine the relationship of these secondary motifs to the immunomodulatory function. Their preliminary data also suggest Muc-1 is able to transduce a signal in addition to its effect on T cells and that the result of this signal is also apoptosis. Thus, the role of Muc-1 as novel regulatory for the cells that express it will be explored with immunoprecipitation following phosphate labeling. Finally, the steroid regulation of Muc-1 will be studied in both breast cancer and myeloma cells in an effort to augment elimination of Muc-1 bearing cells in upcoming Muc-1 vaccination trials.
| Mollick, Joseph A; Hodi, F Stephen; Soiffer, Robert J et al. (2003) MUC1-like tandem repeat proteins are broadly immunogenic in cancer patients. Cancer Immun 3:3 |
| Li, Bibo; de Lange, Titia (2003) Rap1 affects the length and heterogeneity of human telomeres. Mol Biol Cell 14:5060-8 |
