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Tolerance and Immunity to MUC1 in a Human MUC1 Transgenic Murine Model¹

Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259 [G. J. R., S. J. G.], and Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198 [R. M. T., M. L. V., M. A. H.]

The human epithelial mucin, MUC1, is a large transmembrane glycoprotein that is expressed on most simple epithelia. It is overexpressed and aberrantly glycosylated on many human epithelial tumors, including more than 90% of human breast cancers. MUC1 is of interest as an immunotherapy target because patients with breast, ovarian, and pancreatic cancers have T lymphocytes in their tumor-draining lymph nodes that can be induced to recognize and lyse MUC1-expressing tumor cells. We have produced a transgenic mouse model that expresses the human MUC1 molecule on an inbred C57B1/6 background to investigate the effect of endogenous expression of MUC1 on the ability of mice to generate antitumor immunity to MUC1-expressing tumors. Transgenic mice expressed the human transgene in a pattern and level consistent with that observed in humans. Transgenic mice were tolerant to stimulation by MUC1 as evidenced by the ability of MUC1-expressing tumor cells to grow in these mice, whereas MUC1-expressing cells were eliminated from wild-type mice. Moreover, transgenic mice immunized with MUC1 peptides failed to exhibit immunoglobulin class switching to the IgG subtypes. These data suggest that endogenous expression of MUC1 protein by MUC1 transgenic mice induces T-cell tolerance to stimulation by MUC1. The transgenic mice will provide a useful model to investigate the mechanisms that regulate immunological tolerance to tumor antigens and will facilitate the investigation of anti-MUC1 immunotherapy formulations.

¹ This work was supported by the National Cancer Institute, NIH, Grant R01-CA64389 and funds from the Mayo Foundation for Education and Research (to S. J. G.); and by National Cancer Institute, NIH, Grants R01-CA57362, R30 CA36727, and T32 CA09476 and Grant LB 595 from the Nebraska Department of Health (to M. A. H.).

² To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, 13400 E. Shea Boulevard, Scottsdale, AZ 85259.

Received 7/16/97. Accepted 11/11/97.

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