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MANIPULATING DENDRITIC CELL METABOLISM TO PROMOTE CANCER IMMUNITY

操纵树突状细胞代谢以促进癌症免疫

基本信息

批准号：
9133018
负责人：
EDWARD J. PEARCE
金额：
$ 8.1万
依托单位：
INSTITUT FUR IMMUNBIOLOGIE/EPIGENETIK
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9133018
关键词：
5&apos -AMP-activated protein kinase Address Affect Agonist Anti-Inflammatory Agents Anti-inflammatory Asthma Autoimmunity Autologous Dendritic Cells Biology Bone Marrow Carbon Cell Maturation Cells Cellular Metabolic Process Cellular biology Chronic Coupled Data Dendritic Cells Dendritic cell activation Elements Exposure to FRAP1 gene Gene Expression Genes Genetic Glucose Glycolysis Goals Human Immune response Immunity Immunotherapeutic agent Infection Inflammation Interleukin-10 Length Link Longevity Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Mus Natural Immunity Normal tissue morphology Oxidative Phosphorylation Phosphatidylinositols Phosphotransferases Process Property Publishing Research Role T-Lymphocyte Time Toll-like receptors Up-Regulation Vaccination adaptive immunity adenylate kinase aerobic glycolysis base cancer therapy cellular longevity cytokine fatty acid oxidation improved in vivo interest loss of function mTOR inhibition metabolomics mitochondrial metabolism novel strategies pathogen prophylactic receptor research study small molecule therapeutic vaccine tumor upstream kinase vaccination strategy vaccine trial

项目摘要

DESCRIPTION (provided by applicant): We are interested in manipulating the biology of dendritic cells (DCs) in order to enhance or inhibit their ability to induce T cell immunity, which underpins both protective and sometimes deleterious (as is the case in autoimmunity or asthma, for example) immune responses. DCs stand at the interface between innate and adaptive immunity. They express receptors (such as Toll-like receptors, TLRs) that allow them to sense and respond to infection. Following exposure to TLR agonists, which typically are pathogen-derived, quiescent DCs become activated through a process that encompasses changes in expression of genes including those that initiate inflammation and allow DCs to activate naive T cells and thereby stimulate adaptive immune responses. The impact of activated DCs, which is potentially dangerous, is tightly regulated by cytokines such as IL-10, and by a poorly understood mechanism through which cellular lifespan is limited following exposure to TLR agonists. It is increasingly clear that changes in cellular longevity and activation are coupled to profound changes in metabolism. Consistent with this, we have found that the transition of mouse bone marrow-derived DCs from quiescent to activated states involves a significant and prolonged upregulation of aerobic glycolysis and a concomitant decrease in mitochondrial oxidative phosphorylation. Importantly, depriving DCs of glucose or promoting mitochondrial metabolism inhibits activation, suggesting that glycolysis is permissive for DC activation whereas mitochondrial metabolism is not. Collectively, our data implicate DC metabolic reprogramming as an integral component of the activation process. However, we have yet to experimentally address why activation requires such a metabolic switch, or why cellular lifespan is shortened once this switch has occurred, or whether the observed metabolic changes occur in mouse DCs that develop in vivo, or in human DCs. Based on our published and preliminary data, we hypothesize that either: 1) glycolysis is the only type of metabolism that can support the demands of activation, or 2) activated DCs switch to glycolysis because mitochondrial metabolism shuts down as a result of activation. We plan to explore these possibilities in detail through the following specific aims: 1) To determine why TLR-mediated activation of DCs is accompanied by a switch to glycolysis; 2) To explore the role of mitochondrial function and AMP-kinase in DC activation and survival; 3) To promote DC lifespan and sustained expression of costimulatory molecules through the manipulation of metabolic pathways. Our long term goal is to be able to manipulate metabolic processes in DCs in order to promote or inhibit their activation and/or longevity, and in so doing develop novel approaches for improving vaccination strategies, and limiting immune responses in chronic, pathological conditions.

描述（由申请人提供）：我们感兴趣的是操纵树突状细胞（DC）的生物学，以增强或抑制其诱导T细胞免疫的能力，支持保护性和有时有害的（例如，在自身免疫或哮喘的情况下）免疫应答。树突状细胞处于先天免疫和适应性免疫之间的界面。它们表达受体（如Toll样受体，TLR），使它们能够感知并对感染做出反应。在暴露于TLR激动剂（其通常是病原体来源的）之后，静止DC通过包括基因表达变化的过程而被激活，所述基因包括引发炎症并允许DC激活初始T细胞从而刺激适应性免疫应答的那些基因。活化的DC的影响是潜在危险的，受到细胞因子如IL-10的严格调节，并且受到一种知之甚少的机制的调节，通过这种机制，细胞寿命在暴露于TLR激动剂后受到限制。越来越清楚的是，细胞寿命和激活的变化与细胞周期的变化有关。新陈代谢的深刻变化。与此一致，我们发现小鼠骨髓来源的DC从静止状态到活化状态的转变涉及有氧糖酵解的显著和延长的上调以及伴随的线粒体氧化磷酸化的减少。重要的是，剥夺DC的葡萄糖或促进线粒体代谢抑制活化，表明糖酵解允许DC活化，而线粒体代谢则不允许。总的来说，我们的数据暗示DC代谢重编程作为激活过程的一个组成部分。然而，我们还没有通过实验来解决为什么激活需要这样的代谢开关，或者为什么一旦发生这种开关，细胞寿命就会缩短，或者观察到的代谢变化是否发生在体内发育的小鼠DC或人类DC中。基于我们发表的和初步的数据，我们假设：1）糖酵解是唯一可以支持激活需求的代谢类型，或者2）激活的DC切换到糖酵解，因为线粒体代谢由于激活而关闭。我们计划通过以下具体目标详细探索这些可能性：1）确定为什么TLR介导的DC活化伴随着糖酵解的转变; 2）探索线粒体功能和AMP激酶在DC活化和存活中的作用; 3）通过操纵代谢途径促进DC寿命和共刺激分子的持续表达。我们的长期目标是能够操纵DCs中的代谢过程，以促进或抑制其活化和/或寿命，并在这样做的过程中开发用于改善疫苗接种策略和限制慢性病理条件下的免疫应答的新方法。