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) 的五年生存率是所有主要癌症中最差的。的 PDA 的致死率很大程度上是由于缺乏有效的治疗方案。 PDA 治疗的几个障碍是 这是由于免疫抑制性骨髓细胞的存在所赋予的，这些细胞在这些肿瘤中具有很高的代表性。 这种主要由骨髓细胞驱动的免疫抑制使得 PDA 对免疫治疗产生耐药性。 已被证明对其他实体瘤有效。因此，这些骨髓细胞的消除或重新编程 为 PDA 患者的治疗提供急需的突破的潜在途径。 该提案的工作假设是，驱动免疫的代谢机制的中断 抑制将使胰腺癌对免疫疗法敏感。这将分三个部分进行研究。一、核心 由 PDA 细胞编程的骨髓细胞中的代谢途径将被确定，并且这些途径的需求 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 将使用人类和小鼠共培养、类器官和体内研究介导免疫抑制 系统（目标 2）。最后，这些相互作用将与检查点抑制剂一起针对肿瘤模型 确定这些方法的转化价值（目标 3）。 该职业发展奖的指导阶段将由博士监督。科斯塔斯·利西奥蒂斯和卫平 邹教授是密歇根大学医学院的教授。此外，博士。加布里埃尔·努涅斯、玛丽娜·帕斯卡·迪·马利亚诺、 查尔斯·布兰特（Charles Burant）将担任博士后顾问委员会。导师团队共同提出了 职业发展计划侧重于研究、合作、资助、演讲、指导和 获得运行独立研究项目所需的管理技能。这将被执行 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.