MANIPULATING DENDRITIC CELL METABOLISM TO PROMOTE CANCER IMMUNITY

操纵树突状细胞代谢以促进癌症免疫

• 批准号: 8677812
• 负责人: EDWARD J. PEARCE
• 金额: $ 37.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677812
• 关键词: 5' -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 biology; Chronic; Coupled; Data; Dendritic Cells; Dendritic cell activation; Elements; Exposure to; 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; human FRAP1 protein; improved; in vivo; interest; loss of function; mTOR inhibition; metabolomics; novel strategies; pathogen; prophylactic; receptor; research study; small molecule; therapeutic vaccine; tumor; upstream kinase; vaccination strategy

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）：我们对操纵树突状细胞（DC）的生物学感兴趣，以增强或抑制它们诱导 T 细胞免疫的能力，这 支撑保护性的、有时是有害的（例如自身免疫或哮喘的情况）免疫反应。 DC 处于先天免疫和适应性免疫之间的界面。它们表达受体（例如 Toll 样受体，TLR），使它们能够感知感染并做出反应。在接触 TLR 激动剂（通常来自病原体）后，静止的 DC 会通过一个包含基因表达变化的过程而被激活，其中包括那些引发炎症并允许 DC 激活初始 T 细胞，从而刺激适应性免疫反应的基因。活化的 DC 的影响具有潜在的危险，它受到 IL-10 等细胞因子的严格调控，并且受到一种人们知之甚少的机制的严格调控，通过该机制，暴露于 TLR 激动剂后细胞寿命受到限制。越来越清楚的是，细胞寿命和激活的变化与 新陈代谢的深刻变化。与此一致的是，我们发现小鼠骨髓来源的 DC 从静止状态向激活状态的转变涉及有氧糖酵解的显着且长期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会抑制激活，这表明糖酵解允许 DC 激活，而线粒体代谢则不然。总的来说，我们的数据表明 DC 代谢重编程是激活过程的一个组成部分。然而，我们尚未通过实验来解决为什么激活需要这样的代谢转换，或者为什么一旦发生这种转换细胞寿命就会缩短，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。根据我们已发表的初步数据，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，因为线粒体代谢因激活而关闭。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 激活伴随着糖酵解的转变； 2）探讨线粒体功能和AMP激酶在DC激活和存活中的作用； 3）通过操纵代谢途径来促进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树突状细胞中的代谢过程，以促进或抑制它们的激活和/或寿命，并以此开发新的方法来改进疫苗接种策略，并限制慢性病理条件下的免疫反应。