Metabolic checkpoint in dendritic cell subsets and adaptive immunity

程序描述/摘要 树突状细胞(DC)是T细胞免疫和耐受的中枢调节细胞。传统型1或CD8型α+ DC(CDc1)通过递呈抗原给CD8细胞毒性T细胞并刺激抗肿瘤免疫起关键作用 它们在肿瘤内的扩张和效应功能，而cDC1功能直接与免疫相关。 介导性肿瘤排斥反应和免疫治疗的成功。旨在增强cDC1功能的治疗方法 可能因此增强抗肿瘤免疫，并潜在地增加癌症患者对 免疫疗法，如检查站封锁。尽管cDC1的谱系特异性转录调控因子 像BATF3这样的发展已经被确定，分子通路和细胞过程 选择性地协调cDC1功能仍然定义不清。代谢重编程对DC很重要 DC亚群的发育和激活，但对DC亚群的代谢依赖性和调节未知。我们有 开发了一种新的数据驱动系统生物学算法(NetBID)来识别DC子集中的“隐藏”驱动因素， 并发现河马通路激酶Mst1和Mst2(Mst1/2)在选择性地 Cdc1功能和新陈代谢编程。NetBID分析显示，活动显著丰富 CDC1型和CD8型α−树突状细胞(CDC2型)的河马信号通路的差异。删除中的Mst1/2 DC干扰CD8 T细胞功能和抗肿瘤免疫。Mst1/2缺陷的cDC1但不是cDC2受损 体内和体外对CD8T细胞的激活作用。从机理上讲，cDc1表现出更强的氧化磷酸化 (OXPHOS)和严重依赖Mst1/2信号来维持生物能量活动和 功能能力的线粒体动力学。因此，我们假设 河马/MST信号和线粒体活动协调cDC1中独特的代谢检查点 CD8T细胞直接反应与抗肿瘤免疫目的1.在肿瘤树突状细胞中建立Mst1/2信号转导通路 抗肿瘤免疫。目的2.建立DC亚群的线粒体功能及代谢调控。目标3. 确定DC亚群中的河马通路和信号通路。几乎没有对这一事件的描述 控制DC亚群独特功能的分子途径或代谢程序。我们预测我们的 研究将建立DC生物学和免疫代谢的新范式，有可能转化为 癌症治疗的创新策略。

Program Description/Abstract Dendritic cells (DCs) are the central regulators of T cell immunity and tolerance. Conventional type 1 or CD8α+ DCs (cDC1) are critical for anti-tumor immunity by presenting antigens to CD8 cytotoxic T cells and stimulating their expansion and effector function within tumors, and cDC1 function is directly associated with immune- mediated tumor rejection and the success of immunotherapies. Therapies aimed at enhancing cDC1 function may therefore boost anti-tumor immunity and potentially increase the responsiveness of cancer patients to immunotherapies such as checkpoint blockade. Although lineage-specific transcriptional regulators of cDC1 development such as Batf3 have been identified, the molecular pathways and cellular processes that selectively orchestrate cDC1 function remain poorly defined. Metabolic reprogramming is important for DC development and activation, but metabolic dependence and regulation of DC subsets are unknown. We have developed a novel data-driven systems biology algorithm (NetBID) to identify ‘hidden’ drivers in DC subsets, and discovered an unexpected role of Hippo pathway kinases, Mst1 and Mst2 (Mst1/2), in selectively programming cDC1 function and metabolism. The NetBID analysis reveals a marked enrichment of the activity of Hippo pathway kinases in cDC1 relative to conventional type 2 or CD8α− DCs (cDC2). Deletion of Mst1/2 in DCs disrupts CD8 T cell function and anti-tumor immunity. Mst1/2-deficient cDC1 but not cDC2 are impaired in priming CD8 T cells in vivo and in vitro. Mechanistically, cDC1 show much stronger oxidative phosphorylation (OXPHOS) and are critically dependent upon Mst1/2 signaling to maintain bioenergetic activities and mitochondrial dynamics for functional capacities. We therefore hypothesize that the interplay between Hippo/Mst signaling and mitochondrial activity orchestrates a unique metabolic checkpoint in cDC1 to direct CD8 T cell responses and anti-tumor immunity. Aim 1. Establish Mst1/2 signaling in tumor DCs and anti-tumor immunity. Aim 2. Establish mitochondrial function and metabolic control of DC subsets. Aim 3. Determine Hippo pathway and signaling circuits in DC subsets. There has been little description of the molecular pathways or metabolic programs that control the unique function of DC subsets. We predict our studies will establish a new paradigm in DC biology and immunometabolism with the potential to translate into innovative strategies for cancer treatment.