Author

Johnie Hodge

Date of Award

Fall 2018

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Daping Fan

Abstract

Breast cancer is the most common cancer in women worldwide, and is the second leading cause of cancer-related death in spite of significant advances in treatment and emphasis on early diagnosis. While treatment of localized disease is often successful, metastatic breast cancer, especially of the triple negative molecular subtype, carries a much poorer prognosis. The significant role of the immune system in the progression from localized to metastatic disease is becoming more and more appreciated. Tumor escape from immune surveillance and immune suppression in the tumor microenvironment have become therapeutic targets in addition to the traditional goals of directly killing tumor cells. A number of immune therapeutic strategies have been proposed and tested, but few have seen clinical application in the treatment of breast cancer. The development of successful breast cancer immunotherapeutic strategies depends on the rapid identification of immunogenic antigens, timely delivery of these antigens by the optimal vehicle to induce a robust immune response, and appropriate combination with other therapies such as adjuvants, innate immune therapies, and the current standard-of-care treatments. This will allow for more comprehensive targeting of the breast cancer immune regulatory network and likely lead to improved therapeutic success. In the following experiments, two immune therapies which address elements of this multipronged approach will be investigated. The models in which these therapies are tested for gross phenotypic effect are intended to bring basic murine models of experimentation closer to the patterns of future clinical application. The first of these

therapies is emodin, a natural, small molecule compound derived from several Chinese herbs. Its immune modulatory properties have been demonstrated in a number of disease models, but our lab was the first to show that it is capable of attenuating breast cancer progression by blocking the interactions between tumor-associated macrophages and cancer cells. Here emodin is tested as an adjuvant therapy following primary tumor surgical removal for the purpose of preventing metastatic recurrence in a model of murine triple negative breast cancer. We show that trough interfering with TGF-β1 signaling, emodin is capable of decreasing the ability of tumor cells to invade and establish themselves at metastatic sites, thereby reducing metastatic recurrence and increasing overall survival. In addition to its ability to disrupt the reciprocal signaling between tumor cells and macrophages, emodin’s low cost and proven low toxicity make it a promising innate immune therapy. The second therapeutic strategy focuses on improving the effectiveness of dendritic cell-based therapeutic cancer vaccines. Our lab was the first to reveal the role of microRNA-155 (miR155) as a key regulator of dendritic cell function. Our previous work has shown that total-body knockout of miR155 increased both tumor growth and metastasis in an orthotopic model of murine breast cancer. Our therapeutic goal is to increase the presence of miR155 in the immune cells of the tumor microenvironment, most importantly in dendritic cells. Here, total immune system overexpression of miR155 and a miR155-overexpressed DC vaccination therapy are shown to reduce breast tumor growth and metastasis by boosting cytotoxic T cell activity through it multiple positive effects on dendritic cell maturation and migration to tumor-draining lymph nodes. From the results detailed here, both of these strategies hold promise as valuable elements of future combination immune therapies for breast cancer.

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