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: 9067234
• 负责人: EDWARD J. PEARCE
• 金额: $ 23.94万
• 依托单位: INSTITUT FUR IMMUNBIOLOGIE/EPIGENETIK
• 依托单位国家: 美国
• 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/9067234
• 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 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; 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 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

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）：我们有兴趣操纵树突细胞（DC）的生物学，以增强或抑制其诱导T细胞免疫的能力，这 支持保护性，有时甚至是有害的基础（例如自身免疫或哮喘）免疫反应。 DC站在先天和适应性免疫之间的界面。它们表达受体（例如类似收费的受体，TLR），使它们能够感知并反应感染。暴露于通常是病原体衍生的TLR激动剂之后，静态DC通过一个过程，该过程包含基因表达的变化，包括那些引发炎症并允许DC激活天真T细胞的过程，从而刺激自适应免疫反应。活化的DC的影响是潜在的危险的，受IL-10等细胞因子的严格调节，以及通过暴露于TLR激动剂后细胞寿命有限的机制较低的机制。越来越清楚的是，细胞寿命和激活的变化耦合 新陈代谢的深刻变化。与此相一致，我们发现小鼠骨髓衍生的DC从静止状态转变为活化状态，涉及有氧糖酵解的显着且延长的上调，并伴随着线粒体氧化磷酸化的同时降低。重要的是，剥夺DC的葡萄糖或促进线粒体代谢会抑制激活，这表明糖酵解是DC激活的允许的，而线粒体代谢却没有。总的来说，我们的数据将直流代谢重编程视为激活过程中不可或缺的组成部分。但是，我们尚未在实验上解决为什么激活需要这样的代谢开关，或者为什么发生这种开关后缩短细胞寿命，或者在体内发生的小鼠DC中发生观察到的代谢变化，还是在人类DC中发生。根据我们发布的和初步的数据，我们假设要么：1）糖酵解是唯一可以支持激活需求的代谢类型，或2）激活的DCS转向糖酵解，因为线粒体代谢因激活而关闭。我们计划通过以下特定目的详细探讨这些可能性：1）确定为什么TLR介导的DC激活伴随着糖酵解的切换； 2）探索线粒体功能和AMP激酶在直流激活和存活中的作用； 3）通过操纵代谢途径来促进DC寿命和持续表达共刺激分子。我们的长期目标是能够操纵DC中的代谢过程，以促进或抑制其激活和/或寿命，从而开发新的方法来改善疫苗接种策略，并限制慢性病理状况的免疫反应。