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。宿主免疫系统不能产生有效的抗肿瘤反应已得到充分证实。髓系细胞的凋亡是其发生的主要机制之一。为了更好地了解这些异常的性质，我们集中研究了脂质代谢在癌症中髓样细胞功能调节中的作用。我们最近发现，在癌症患者和荷瘤小鼠中的DCs比在无肿瘤宿主中的DCs具有更高的脂质含量。我们已经发现DC中脂质的积累对其处理和呈递抗原以及刺激免疫应答的能力具有深远的负面影响。在本申请中，我们提出了一个新的概念，即癌症中骨髓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作为肿瘤微环境中氧化脂质（ox-lipids）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和大量氧化，然后在与T细胞密切接触期间有助于这些细胞的免疫抑制活性，干扰MDSC分化为成熟的骨髓细胞并促进其凋亡。死亡的MDSC释放大量氧化脂质到细胞外环境中，在那里它们可以整合到脂蛋白中并被DC拾取。氧化修饰的脂质通过DC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，那么靶向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是为了更好地理解 癌症中调节骨髓细胞功能的机制，但开发新的方法来调节癌症中的免疫反应。为了实现这一目标，我们提出以下具体目标：具体目标1。明确骨髓细胞中脂质蓄积和氧化的性质和机制。利用质谱分析，我们将确定癌症中骨髓细胞中积累的脂质的性质。我们将确定机制的脂质积累在MDSC和负责这些细胞中的脂质氧化的因素。具体目标2。确定髓系细胞中脂质蓄积的功能后果。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。我们将探讨高脂含量DC异常抗原提呈的机制。具体目标3。探讨骨髓细胞中脂质积聚在癌症中的转化作用。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中脂质积聚的治疗性化合物对荷瘤小鼠中对疫苗接种的免疫应答的影响。

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.