Metabolic checkpoint in dendritic cell subsets and adaptive immunity

项目描述/摘要 树突状细胞（Dendritic cells，DC）是T细胞免疫和耐受的主要调节者。常规1型或CD 8 α+ DC（cDC 1）通过向CD 8细胞毒性T细胞呈递抗原并刺激CD 8细胞毒性T细胞的增殖而对抗肿瘤免疫至关重要。 它们在肿瘤内的扩增和效应子功能，而cDC 1的功能与免疫相关。 介导的肿瘤排斥和免疫疗法的成功。旨在增强cDC 1功能的疗法 因此可能增强抗肿瘤免疫力，并可能增加癌症患者对 免疫疗法，如检查点阻断。尽管cDC 1的谱系特异性转录调节因子 已经确定了诸如Batf 3的分子途径和细胞过程， 选择性地协调cDC 1功能仍然不清楚。代谢重编程对DC很重要 但是DC亚群的代谢依赖性和调节是未知的。我们有 开发了一种新的数据驱动的系统生物学算法（NetBID），以识别DC子集中的“隐藏”驱动程序， 并发现了Hippo通路激酶Mst 1和Mst 2（Mst 1/2）在选择性地 编程cDC 1功能和代谢。NetBID分析显示， cDC 1中Hippo通路激酶相对于传统2型或CD 8 α− DC（cDC 2）的变化。删除Mst 1/2， DC破坏CD 8 T细胞功能和抗肿瘤免疫。Mst 1/2缺陷型cDC 1受损，但cDC 2未受损， 在体内和体外引发CD 8 T细胞。从机制上讲，cDC 1显示出更强的氧化磷酸化作用， （OXPHOS），并严重依赖于Mst 1/2信号传导，以维持生物能量活动， 线粒体动力学的功能能力。因此，我们假设， Hippo/Mst信号传导和线粒体活性协调cDC 1中的独特代谢检查点， 直接的CD 8 T细胞应答和抗肿瘤免疫。目标1.在肿瘤DC中建立Mst 1/2信号传导， 抗肿瘤免疫目标2.建立DC亚群的线粒体功能和代谢控制。目标3. 确定DC亚群中的Hippo通路和信号通路。几乎没有关于 控制DC亚群独特功能的分子途径或代谢程序。我们预测， 研究将建立DC生物学和免疫代谢的新范式，并有可能转化为 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.