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Characterization of the Cytotoxic CD8+ T Cell Immune Response to Mammaglobin-A
Tumor Cell Biology III
Background: A novel breast cancer-associated antigen, mammaglobin-A, has recently been identified in our laboratory. Unlike other genes expressed by breast tumors, the over-expression of mammaglobin-A is breast cancer-specific. Another significant finding is that 80% of primary breast tumors have high levels of mammaglobin-A expression. Our recent studies have shown that mammaglobin-A-reactive T cells are expanded in breast cancer patients. Also, we were able to identify several mammaglobin-A-derived epitopes. Further, CD8+ cytotoxic T lymphocyte (CTL) lines generated against these epitopes had the ability to lyse mammaglobin-A+ breast cancer cells lines. In addition, HLA-A2+/human CD8+ mice vaccinated with mammaglobin-A cDNA recognized a similar epitope pattern as HLA-A2+ breast cancer patients and showed a significant CD8+ CTL activity against HLA-A2+ human breast cancer cell lines. Hypothesis: Our hypothesis is that vaccination of with mammaglobin-A epitope cDNA constructs will induce CD4+ and/or a CD8+ T cell immune responses capable of inducing regression of established breast tumors. Specific aims: Our specific aims are to develop a new strategy for cDNA vaccination using constructs containing the coding regions for single mammaglobin-A CD4+ and CD8+ T cell epitopes. Methods: Either HLA-DR4-transgenic or HLA-A2-trangenic mice will be vaccinated using different mammaglobin-A epitope cDNA constructs. The ability of CD4+ and CD8+ T cells from immunized mice to lyse human HLA-DR4+ and HLA-A2+ breast cancer cell lines respectively will be analyzed. The ability of CD4+ and CD8+ T cells from these mice to induce the regression of tumors established in SCID beige mice will also be analyzed in adoptive transfer experiments. Relevance: These studies will directly influence patient care as follows: by using these humanized mouse models (HLA-DR4- and HLA-A2-transgenic mice), we will be able to test the efficacy of a mammaglobin-A epitope vaccine in preventing the growth of human breast tumors in vivo .
Approximately 11% of American women will develop breast cancer by the age of 85. The treatment for most patients is surgical removal of the tumor and chemotherapy. In spite of improvements in therapy, the survival of breast cancer patients that show advanced or metastatic disease is still very poor. This demonstrates the need for new approaches in breast cancer therapy and in identification of individuals at high risk. The understanding of the immune response to breast cancer should be of great help in the development of new therapies for the treatment of this disease. We have identified a protein, mammaglobin-A, that is exclusively expressed on breast cancer cells. In addition, we have demonstrated that mammaglobin-A is recognized by lymphocytes that have the ability to kill tumor cells. In our proposal will determine the potential use of mammaglobin-A vaccination for the generation of a protective breast cancer-specific lymphocyte response and to develop a new strategy for vaccination using DNA. Specially bred mice containing human immune recognition proteins will be used for these studies. The ability of lymphocytes from vaccinated mice to kill human breast cancer cells and to induce the regression of already existing breast tumors will be analyzed. Since mammaglobin-A is exclusively expressed by breast cancer tissue, the injection of lymphocytes that recognize mammaglobin-A into breast cancer patients could induce tumor regression without danger to other normal tissues. Moreover, a mammaglobin-A vaccine could be used to induce a protective immune response in breast cancer patients after removal of the tumor to prevent recurrence. In conclusion, these studies may lead to the development of a breast cancer-specific vaccine to be utilized as immunomodulatory therapy both for treatment and for prevention of breast cancer. Also, with the understanding of the lymphocyte reactivity against mammaglobin-A, we may be able to identify patients at high risk for primary disease development or recurrence after surgical removal of the tumor.