Project 2-Metabolic Modulation of Myeloid-Derived Suppressor Cells to Increase Efficacy of Neo adjuvant Chemotherapy and Immunotherapy

摘要 路易斯安那州非裔美国人(AA)女性中三重阴性乳腺癌(TNBC)的发病率为 大约是欧美(EA)女性的两倍。演讲的高级阶段， 激素受体缺失和对新辅助化疗的不良反应对 这对这些患者的结果是不利的，并进一步加剧了这种疾病的健康差距。因此，识别 提高新辅助化疗或新型免疫疗法疗效的方法可能会有所改进 这些患者的生存，并可以在一定程度上开始解决这种不平等。慢性炎性髓系细胞 在肿瘤微环境中，以髓系来源的抑制细胞(MDSC)为代表的抗肿瘤效应 化疗、放射治疗和免疫治疗。以前使用以下方法耗尽MDSC的方法 化疗或酪氨酸激酶抑制剂已被证明可以提高治疗效果 化疗和免疫治疗。然而，这些方法只会产生短期的持久影响。我们的数据 相反，表明MDSC依赖于脂类代谢来支持其功能，包括生产 精氨酸酶I，它们的主要免疫抑制机制。阻断脂肪酸氧化或精氨酸酶I抑制 MDSC的功能，并显著增强化疗和免疫治疗的疗效。我们的数据 表明这可以通过重新调整用途的药物或新型精氨酸酶I抑制剂来实现。项目2将 证实MDSC浸润性人TNBC肿瘤依赖于脂代谢，并将决定 如果它们对这些通路的抑制剂敏感。同样，使用TNBC的小鼠模型，我们将测试 脂代谢抑制剂或精氨酸酶I联合应用时有协同治疗作用 化疗或免疫治疗。特异性脂代谢和精氨酸酶I抑制剂的可用性 使拟议的研究更加重要，因为它促进了临床试验的发展 未来孢子的应用前景。

ABSTRACT 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.