Lipids and Myeloid Cell Function in Cancer

描述(申请人提供)：免疫系统在调节肿瘤进展中起关键作用，并深刻影响癌症免疫治疗的成败。宿主免疫系统不能建立有效的抗肿瘤反应是公认的。髓系细胞系的异常是导致这种现象的主要机制之一。为了更好地理解这些异常的本质，我们重点研究了脂质代谢在调节肿瘤髓系细胞功能中的作用。我们最近已经证明，癌症患者和荷瘤小鼠中的DC比无肿瘤宿主中的DC具有显著更高的脂质含量。我们发现，DC中脂质的积累对其处理和呈递抗原以及刺激免疫反应的能力具有深远的负面影响。在这一应用中，我们建议研究一种新的概念，即癌症中髓系细胞的异常在很大程度上是由脂质的积累及其随后的过氧化反应引起的。MDSC是肿瘤微环境中氧化脂质的主要来源，可供包括DC在内的其他细胞使用。我们认为，MDSC中积累的脂质被快速而大量地氧化，在与T细胞密切接触的过程中参与了这些细胞的免疫抑制活性，干扰了MDSC向成熟髓系细胞的分化，并促进了其凋亡。濒临死亡的MDSC释放出大量的氧化脂质进入细胞外环境，在那里它们可以被整合成脂蛋白并被DC摄取。树突状细胞氧化修饰脂质的积累极大地影响了其处理和向T细胞递送可溶性蛋白的能力。如果这一假设是正确的，那么针对癌症患者的脂代谢可能代表着一种有吸引力的治疗策略。这个项目的最终目标不仅是为了更好地了解 在癌症中调节髓系细胞功能的机制，但开发新的方法来调节癌症的免疫反应。为了实现这一目标，我们提出了以下具体目标：具体目标1.鉴定髓系细胞中脂质堆积和氧化的性质和机制。利用质谱仪，我们将鉴定癌症中积聚在髓系细胞中的脂类的性质。我们将确定MDSC中脂质积聚的机制以及导致这些细胞中脂质氧化的因素。具体目的2.确定髓系细胞中脂质积聚的功能后果。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系细胞分化的影响。我们将探讨高脂DC异常提呈抗原的机制。具体目的3.探讨髓系细胞脂质积聚在肿瘤中的翻译作用。我们将研究脂质在癌症患者MDSC和DC功能中的作用。我们将评估靶向细胞内脂质堆积的治疗化合物对荷瘤小鼠接种疫苗的免疫反应的影响。

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.