The incidence of triple negative breast cancer (TNBC) in African American (AA) women in Louisiana is approximately double that of European America (EA) women. The advanced stage at presentation, the absence of hormonal receptors and the poor response to neoadjuvant chemotherapy negatively impact the outcome for these patients and further worsens the health disparity of this disease. Therefore identifying approaches that improve the efficacy of neoadjuvant chemotherapy or novel immunotherapies may improve survival in these patients, and could in part start to address this inequality. Chronic inflammatory myeloid cells in the tumor microenvironment, represented by myeloid derived suppressor cells (MDSC) impair the efficacy of chemotherapy, radiation therapy and immunotherapy. Previous approaches to deplete MDSC using chemotherapy or tyrosine kinase inhibitors have been shown to enhance the therapeutic efficacy of chemotherapy and immunotherapy. However these approaches have only short term lived effects. Our data instead show that MDSC are dependent on lipid metabolism to support their functions, including the production of arginase I, their primary immunosuppressive mechanism. Blocking fatty acid oxidation or arginase I inhibits the function of MDSC, and significantly potentiates the efficacy of chemotherapy and immunotherapy. Our data show that this can be achieved with repurposed drugs or with novel arginase I inhibitors. Project 2 will demonstrate that MDSC infiltrating human TNBC tumors are dependent on lipid metabolism and will determine if they are sensitive to inhibitors of these pathways. Similarly, using murine models of TNBC, we will test if the inhibitors of lipid metabolism or arginase I have a synergistic therapeutic effect when combined with chemotherapy or immunotherapy. The availability of the specific lipid metabolism and arginase I inhibitors makes the proposed research even more significant since it facilitates the development of clinical trials for a future SPORE application.
Chronic inflammation in the form of myeloid-derived suppressor cells (MDSC) decreases the therapeutic efficacy of chemotherapy, radiation therapy and immunotherapy in cancer, including triple-negative breast cancer (TNBC). Multiple approaches to eliminate MDSC, including high dose chemotherapy, have not been successful, but our data suggests that the use of lipids or inhibiting arginase I inhibits MDSC and enhances the efficacy of chemotherapy and immunotherapy. Project 2 will test whether similar approaches in TNBC block the negative effects of MDSC and show synergy with chemotherapy and immunotherapy, thus improving the outcome for this malignancy, which disproportionately affects African-American women.
