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

项目2-骨髓源性抑制细胞的代谢调节以提高新辅助化疗和免疫疗法的疗效

• 批准号: 10005254
• 负责人: AUGUSTO C. OCHOA
• 金额: $ 27.1万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005254
• 关键词: Address; Adjuvant Chemotherapy; Affect; African American; Americas; Antitumor Response; Bone Marrow; Breast Cancer Patient; Cancer Patient; Cardiovascular Diseases; Chemotherapy and/or radiation; Chronic; Clinical Trials; Data; Death Rate; Development; Disease; Enzymes; European; Fatty Acids; Fluorouracil; Future; Grant; High Dose Chemotherapy; Hormonal; Human; Immunosuppression; Immunotherapy; Impairment; In Vitro; Incidence; Inequality; Infiltration; Inflammation; Inflammatory; Intervention; Lipids; Louisiana; Malignant Neoplasms; Mental disorders; Metabolic; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Neoadjuvant Therapy; Nitric Oxide; Oral; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Production; Publishing; Radiation therapy; Research; Role; Suppressor-Effector T-Lymphocytes; T cell response; Testing; Therapeutic Effect; Treatment Efficacy; Tyrosine Kinase Inhibitor; Woman; Work; advanced disease; antitumor effect; arginase; cancer health disparity; chemotherapy; clinical development; efficacy testing; fatty acid oxidation; gemcitabine; health disparity; improved; improved outcome; in vivo; inhibitor/antagonist; lipid metabolism; malignant breast neoplasm; mouse model; novel; novel strategies; outcome forecast; oxidized lipid; peripheral blood; receptor; response; synergism; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; uptake

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.

摘要 路易斯安那州非裔美国人（AA）妇女的三阴性乳腺癌（TNBC）发病率为 这一比例几乎是欧美女性的两倍。在介绍的高级阶段， 激素受体的缺乏和对新辅助化疗的不良反应对 这些患者的结果，并进一步评估这种疾病的健康差异。因此， 提高新辅助化疗或新型免疫疗法疗效的方法可能会改善 这些患者的生存率，并可以部分开始解决这种不平等。慢性炎性骨髓细胞 在肿瘤微环境中，以髓源性抑制细胞（MDSC）为代表的肿瘤微环境损害了 化疗、放疗和免疫疗法。先前使用以下方法消耗MDSC的方法 化疗或酪氨酸激酶抑制剂已经显示出增强 化疗和免疫疗法。然而，这些方法只有短期的效果。我们的数据 相反，显示MDSC依赖于脂质代谢来支持其功能，包括产生 它们的主要免疫抑制机制。阻断脂肪酸氧化或脂肪酶I抑制 MDSC的功能，并显着增强化疗和免疫治疗的疗效。我们的数据 表明这可以通过改变用途的药物或新的辅酶I抑制剂来实现。项目2将 证明MDSC浸润人TNBC肿瘤依赖于脂质代谢，并将决定 如果他们对这些通路的抑制剂敏感的话。类似地，使用TNBC的鼠模型，我们将测试TNBC是否具有免疫原性。 脂质代谢抑制剂或脂质体酶I抑制剂在与 化疗或免疫疗法。特异性脂代谢和脂酶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， 未来的应用。