Lipids and Myeloid Cell Function in Cancer

癌症中的脂质和骨髓细胞功能

• 批准号: 8927544
• 负责人: Dmitry I Gabrilovich
• 金额: $ 35.74万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927544
• 关键词: Abnormal Cell; Address; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Cancer Etiology; Cancer Patient; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Data; Dendritic Cells; Environment; Failure; Goals; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunotherapy; Lipids; Lipoproteins; Lipoxygenase; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mus; Myelogenous; Myeloid Cells; Nature; Nonesterified Fatty Acids; Peroxidases; Play; Process; Proteins; Publishing; Reactive Oxygen Species; Regulation; Reporting; Research; Role; Source; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Therapeutic; Therapeutic Effect; Up-Regulation; Vaccination; base; extracellular; lipid metabolism; macrophage; macrophage scavenger receptors; novel; novel strategies; oxidation; oxidized lipid; peroxidation; receptor; scavenger receptor; success; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Immune system plays a critical role in regulation of tumor progression and profoundly influences the success or failure of cancer immune therapy. Inability of host immune system to mount potent antitumor resposnes is well established. Abnormalities in myeloid cell lineage is one of the major mechanisms of this phenomenon. In an attempt to better undertsdant the nature of these abnormalities we have focused on the role of lipid metbolism in regulation of myeloid cell function in cancer. We have recently demonstrated that DCs in cancer pateints and in tumor-bearing mice had substantially higher lipid content than their counterparts in tumor-free hosts. We have found that accumulation of lipids in DCs have profound negative implications for their ability to process and present antigens and stimulate immune responses. In this application we propose to investigate a novel concept that abnormalities in myeloid cells in cancer are caused, to a large extent, by accumulation of lipids and their subsequent peroxidation. MDSC serves as a major source of oxidized lipids (ox-lipids) in tumor microenvironment that become available for other cells including DCs. We propose that lipids accumulated in MDSC are quickly and massively oxidized and then contribute to immune suppressive activity of these cells during close contact with T cells, interfere with MDSC differentiation to mature myeloid cells and promote their apoptosis. Dying MDSC release large quantities of ox-lipids into extracellular environment where they can be integrated into lipoproteins and picked up by DCs. Accumulation of oxidatively modified lipids by DCs dramatically affects their ability to process and present soluble proteins to T cells. If this hypothesis is correct then targeting lipid metabolism in cancer patients could represent an attractive therapeutic strategy. The ultimate goal of this project is not only to better understand the mechanism regulating myeloid cell function in cancer but to develop novel approaches to regulation of immune responses in cancer. To achieve this goal we propose the following specific aims: Specific aim 1. To identify the nature and the mechanisms of lipid accumulation and oxidation in myeloid cells. Using mass-spectrometry we will identify the nature of lipids accumulated in myeloid cells in cancer. We will identify the mechanism of lipid accumulation in MDSC and factors responsible for lipids oxidation in these cells. Specific aim 2. To determine the functional consequences of lipid accumulation in myeloid cells. We will identify the role of oxidized lipids in MDSC mediated immune suppression and determine the effect of oxidized lipids on differentiation of myeloid cells. We will investigate the mechanism of abnormal antigen presentation by DCs with high lipid content. Specific aim 3. To investigate the translational role of lipid accumulation in myeloid cells in cancer. We will study the role of lipids in the function f MDSC and DCs in cancer patients. We will evaluate the effect of therapeutic compounds targeting lipid accumulation in cells on immune responses to vaccination in tumor- bearing mice.

描述（由申请人提供）：免疫系统在调节肿瘤进展中起着至关重要的作用，并深刻影响癌症免疫治疗的成功或失败。宿主免疫系统无法实现有效的抗肿瘤反应。髓样细胞谱系异常是这种现象的主要机制之一。为了更好地承诺这些异常的性质，我们集中于脂质元质量在调节髓样细胞功能在癌症中的作用。我们最近证明，癌症和含肿瘤小鼠的DC的脂质含量大大高于无肿瘤宿主中的脂质含量。我们发现，DC中脂质的积累对它们的处理能力和抗原和刺激免疫反应具有深远的负面影响。在此应用中，我们建议调查一个新的概念，即通过脂质的积累及其随后的过氧化作用，在很大程度上引起癌症中髓样细胞的异常。 MDSC是肿瘤微环境中氧化脂质（牛脂）的主要来源，可用于包括DC在内的其他细胞。我们提出，在与T细胞密切接触期间，积累在MDSC中的脂质会迅速而大规模氧化，然后有助于这些细胞的免疫抑制活性，从而与MDSC分化与成熟的髓样细胞的分化并促进其细胞凋亡。垂死的MDSC将大量的牛脂释放到细胞外环境中，可以将它们整合到脂蛋白中并被DC拾取。 DCS的氧化脂质累积会极大地影响其处理并将可溶性蛋白呈现给T细胞的能力。如果该假设是正确的，那么靶向癌症患者脂质代谢的靶向可能代表了一种有吸引力的治疗策略。该项目的最终目标不仅是为了更好地理解 调节癌症中髓样细胞功能的机制，但要开发新的方法来调节癌症的免疫反应。为了实现这一目标，我们提出以下特定目的：特定目的1。确定脂质细胞中脂质积累和氧化的性质和机制。使用质谱法，我们将确定癌症中积累的脂质的性质。我们将确定MDSC中脂质积累的机制以及负责这些细胞中脂质氧化的因素。具体目的2。确定髓样细胞中脂质积累的功能后果。我们将确定氧化脂质在MDSC介导的免疫抑制中的作用，并确定氧化脂质对髓样细胞分化的影响。我们将研究具有高脂质含量的DC异常抗原表现的机制。具体目的3。研究脂质积累在髓样细胞中癌症中的转化作用。我们将研究脂质在癌症患者功能F MDSC和DC功能中的作用。我们将评估靶向细胞中脂质积累对肿瘤轴承小鼠疫苗接种的免疫反应的治疗化合物的作用。