Lipids and Myeloid Cell Function in Cancer

描述（申请人提供）：免疫系统在肿瘤的进展调控中起着至关重要的作用，深刻影响着肿瘤免疫治疗的成败。宿主免疫系统不能产生有效的抗肿瘤反应是公认的。髓系细胞谱系异常是这一现象的主要机制之一。为了更好地理解这些异常的本质，我们集中研究了脂质代谢在癌症中调节髓细胞功能中的作用。我们最近证明，癌症患者和荷瘤小鼠中的dc比无肿瘤宿主中的dc具有更高的脂质含量。我们发现脂质在dc中的积累对其加工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。在这个应用中，我们提出研究一个新的概念，即癌症中髓细胞的异常在很大程度上是由脂质积累及其随后的过氧化引起的。MDSC是肿瘤微环境中氧化脂质（ox-脂质）的主要来源，可用于包括dc在内的其他细胞。我们认为，积累在MDSC中的脂质在与T细胞密切接触时被迅速大量氧化，从而促进这些细胞的免疫抑制活性，干扰MDSC向成熟髓细胞的分化并促进其凋亡。死亡的MDSC释放大量的氧脂到细胞外环境中，在那里它们可以整合成脂蛋白并被dc拾取。dc氧化修饰脂质的积累显著影响其加工和向T细胞呈递可溶性蛋白的能力。如果这一假设是正确的，那么针对癌症患者的脂质代谢可能是一种有吸引力的治疗策略。这个项目的最终目的不仅仅是为了更好地理解

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.