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

项目概要/摘要 胰腺导管腺癌（PDA）是所有主要癌症中五年生存率最低的。的 PDA的致命性主要是由于缺乏有效的治疗选择。PDA治疗中的几个障碍是 这是由于存在免疫抑制性髓样细胞，其在这些肿瘤中高度表达。 这种免疫抑制主要由骨髓细胞驱动，使PDA对免疫疗法难以治疗， 在其他实体瘤中有效。因此，这些骨髓细胞的消除或重编程 为PDA患者的治疗提供了急需的突破性进展。 这项建议的工作假设是，中断驱动免疫的代谢机制， 抑制将使胰腺癌对免疫疗法敏感。这将分三个部分加以审查。一是核心 将鉴定由PDA细胞编程的髓样细胞中的代谢途径，并且这些代谢途径的需求将被确定。 将测试程序的功能（目标1）。接下来，这些骨髓细胞的代谢机制 将使用人和鼠共培养、类器官和体内研究介导的免疫抑制。 系统（目标2）。最后，这些相互作用将在与检查点抑制剂偶联的肿瘤模型中靶向 确定这些方法的转化价值（目标3）。 这个职业发展奖的指导阶段将由Costas Lyssiotis博士和Weiping博士监督 密歇根大学医学院的邹博士说。此外，加布里埃尔·努涅斯博士，玛丽娜·帕斯卡·迪·马利亚诺博士， 查尔斯·布兰特将担任博士后顾问委员会。导师团队一起 一个职业发展计划，重点是研究，合作，赠款，演示，指导，和 获得必要的管理技能，以运行一个独立的研究计划。这项工作将在 利用密歇根大学的特殊资源。

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.