Disrupting macrophage metabolism to reduce immunosuppression and enhance therapy in pancreatic cancer

破坏巨噬细胞代谢以减少免疫抑制并增强胰腺癌的治疗

• 批准号: 10245783
• 负责人: Christopher J. Halbrook
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245783
• 关键词: Ablation; Adenocarcinoma Cell; Advisory Committees; Amino Acids; Anti-Inflammatory Agents; Arginine; Attenuated; Automobile Driving; Bioenergetics; Biological Assay; CD8-Positive T-Lymphocytes; Cells; Cessation of life; Clinical; Coculture Techniques; Collaborations; Consumption; Coupled; Cues; Cytotoxic T-Lymphocytes; DTR gene; Data; Development Plans; Diagnosis; Disease; Foundations; Genetic; Goals; Human; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunosuppression; Immunotherapy; Infiltration; Inflammatory; Interruption; Investigation; K-Series Research Career Programs; Ligands; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mentored Clinical Scientist Development Award (K08); Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Michigan; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Nutrient; Organoids; Outcome; PDL1 inhibitors; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Physiology; Positioning Attribute; Production; Refractory; Research; Research Proposals; Resources; Role; Running; S-Phase Fraction; Scheme; Shapes; Signal Pathway; Signal Transduction; Solid Neoplasm; Survival Rate; System; T-Cell Activation; T-Lymphocyte; Testing; Translating; Tumor-associated macrophages; United States; Universities; Work; anticancer activity; arginase; base; cancer cell; career development; conditional knockout; effective therapy; extracellular; genetic approach; immune checkpoint; immune checkpoint blockade; improved; in vivo; inhibitor/antagonist; insight; macrophage; medical schools; metabolomics; mouse model; pancreatic neoplasm; pre-clinical; programmed cell death ligand 1; programs; skills; tumor; tumor microenvironment; tumor-immune system interactions

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDA) has the worst five-year survival rate of any major cancer. The lethality of PDA is largely due to a lack of effective treatment options. Several barriers in PDA treatment are conferred by the presence of immunosuppressive myeloid cells, which are highly represented in these tumors. This immune suppression, driven largely by myeloid cells, renders PDA refractory to immunotherapy which has proven effective in other solid tumors. Consequently, the elimination or reprogramming of these myeloid cells offers potential avenues to provide a much-needed breakthrough for the treatment of patients with PDA. The working hypothesis of this proposal is that interruption of the metabolic mechanisms driving immune suppression will sensitize pancreatic cancer to immunotherapy. This will be examined in three parts. First, core metabolic pathways in myeloid cells programmed by PDA cells will be identified and the requirement of these programs for functionality will be tested (Aim 1). Next, the metabolic mechanisms by which these myeloid cells mediate immune suppression will be investigated using human and murine co-culture, organoid, and in vivo systems (Aim 2). Finally, these interactions will be targeted in tumor models coupled with checkpoint inhibitors to determine the translational value of these approaches (Aim 3). The mentored phase of this career development award will be overseen by Drs. Costas Lyssiotis and Weiping Zou at the University of Michigan Medical School. In addition, Drs. Gabriel Nunez, Marina Pasca di Magliano, and Charles Burant will serve as a postdoctoral advisory committee. Together, the mentorship team has set forth a career development plan focused on research, collaboration, grantsmanship, presentation, mentorship, and the acquisition of management skills necessary to run an independent research program. This will be carried out utilizing the exceptional resources available at the University of Michigan.

项目摘要/摘要 胰腺导管腺癌（PDA）的五年生存率最差。这 PDA的致死性很大程度上是由于缺乏有效的治疗选择。 PDA治疗中的几个障碍 由存在在这些肿瘤中高度代表的免疫抑制性髓样细胞所赋予的。 这种免疫抑制主要由髓样细胞驱动，使PDA对具有的免疫疗法难治性 被证明在其他实体瘤中有效。因此，消除或重编程这些髓样细胞 提供潜在的途径，为PDA患者的治疗提供急需的突破。 该提案的工作假设是，动力免疫的代谢机制的中断 抑制作用将使胰腺癌对免疫疗法敏感。这将分为三个部分。首先，核心 将确定由PDA细胞编程的髓样细胞中的代谢途径，这些要求 功能程序将进行测试（AIM 1）。接下来，这些髓样细胞的代谢机制 将使用人和鼠共培养，器官和体内研究介导免疫抑制 系统（目标2）。最后，这些相互作用将针对与检查点抑制剂相连的肿瘤模型 确定这些方法的翻译价值（AIM 3）。 该职业发展奖的指导阶段将由博士监督。 Costas lyssiotis和Weiping 密歇根大学医学院的Zou。另外，博士。 Gabriel Nunez，Marina Pasca di Magliano， 查尔斯·布兰特（Charles Burant）将担任博士后咨询委员会。指导团队一起提出 职业发展计划的重点是研究，协作，授予技巧，演示，指导和 获得独立研究计划所必需的管理技能。这将进行 利用密歇根大学可用的特殊资源。