Department of Nutrition Sciences and Comprehensive Cancer Center
University of Alabama at Birmingham
Dr. Norian worked with mentor Dr. Paul Allen, Professor in the Department of Pathology, to study the interactions between the immune system and breast cancer. She identified a novel population of regulatory tumor-infiltrating dendritic cells. She published evidence challenging traditional views of immunotherapy for breast cancer in PLoS ONE in September 2007. She was successful at obtaining grant support during her BIRCWH training, including the Department of Defense Breast Cancer Award and American Cancer Society Award. Dr. Norian is an Assistant Professor in the Department of Urology at University of Iowa College of Medicine. She recently demonstrated that obesity suppresses immunotherapy in mouse models of kidney tumors and is translating these findings in to human studies. She recently obtained an RO1 grant to support her research effort.
BIRCWH Scholar from 07/01/2006 to 06/30/2008
Suppression of Antitumor immunity By Mammary Tumor infiltrating Regulatory Dendritic Cells
Breast cancer is the most prevalent type of cancer In women. Although the survival rates for women with non-metastatic cancer have increased in recent years, the prognosis for those individuals with metastatic disease remains poor. Clearly, additional therapeutic regimens are needed. Immunotherapy is a promising adjunct treatment option that seeks to utilize the specificity of the immune system to eradicate tumors. The major obstacle facing successful administration of immunotherapy to treat cancer is that most tumors are profoundly immunosuppressive. The majority of immunotherapeutic protocols currently focus on two types of cells: T lymphocytes and dendritic cells. CD8+ T cells are able to recognize specific antigens on the surface of tumor cells, and kill them. However, to accomplish this, T cells must first be activated by dendritic cells presenting tumor derived antigens. Therefore, normal dendritic cell function is essential for the generation of protective antitumor Immunity. We recently identified a population of dysfunctional dendritic cells in a murine model of spontaneous mammary carcinoma. These tumor-infiltrating dendritic cells are unable to effectively prime naïve CD8+ T cells, resulting in minimal T cell expansion and little IFNy production. More Importantly, tumor infiltrating dendritic cells act in a dominant fashion to suppress T cell activation and proliferation in response to normal, stimulatory dendritic cells. Thus, we have made the novel finding that dendritic cells within spontaneously arising tumors function as regulatory dendritic cells, and inhibit CD8+ T cell function in vitro. Our research thus far has investigated the role of tumor regulatory dendritic cells on naive T cells. It is currently unknown what the effects of regulatory dendritic cells are on previously activated, effector T cells. Additionally, little is known about the factors that lead to the development of regulatory dendritic cells, particularly within tumors. It is also not known whether the suppressive functions of regulatory dendritic cells can be reversed to create a more normal, stimulatory type of dendritic cell. Our hypothesis is that stromal cells within mammary carcinomas lead to the development of regulatory dendritic cells, which then act to suppress CD8+ T cell mediated antitumor Immunity. It is hoped that information gained from these studies could translate into immunotherapies capable of restoring normal function in tumor infiltrating dendritic cells in cancer patients, thereby enhancing the ability of T lymphocytes to protect women from metastatic breast cancer, leading to prolonged survival for these individuals.
1. Determine the consequences of tumor-infiltrating dendritic cell encounter with previously
activated CD8+ T cells in vitro and in vivo.
2. Identify soluble factors in the tumor microenvironment that lead to the generation and accumulation of regulatory DCs within mammary carcinomas.
3. Determine if the suppressive functions of regulatory DCs can be reversed by blockade of STAT3 signal transduction pathways.