Lipids and Myeloid Cell Function in Cancer

项目摘要 骨髓细胞是肿瘤微环境的重要组成部分。在生理条件下，这些细胞 由成熟的终末分化细胞组成：多形核中性粒细胞（PMN）和其他 粒细胞;巨噬细胞（MΦ）;和树突状细胞（DC）。在癌症中，骨髓腔室显著地 受影响，这现在被认为是癌症的主要免疫标志之一。荷瘤 (TB)宿主积累免疫抑制性MΦ，癌症中的DC无法诱导有效的免疫 应答肿瘤中髓样区室的显著变化是病理学上髓样区室的扩张， 激活的未成熟髓系细胞，具有抑制免疫反应的强大能力-髓源性 抑制细胞（MDSC）。在TB小鼠中，MDSC的总群体由三组细胞组成： 最丰富（>75%）的未成熟病理活化中性粒细胞（PMN-MDSC）;较少丰富（<20%） 病理活化的单核细胞群-（M-MDSC）;和小的（<5%）早期髓样细胞群-（M-MDSC）。 前体目前的观点分别考虑骨髓细胞的变化。不同的机制适用于 不同的细胞。我们知识上的差距是这些不同的骨髓细胞如何相互作用 在荷瘤宿主中。在这个建议中，我们将测试氧化脂质可能提供桥梁的假设， 在癌症中不同群体的骨髓细胞之间，协调它们的异常功能。 该项目的最终目的不仅是更好地了解调节髓系细胞的机制， 除了开发调节癌症免疫反应的新方法之外，还需要研究癌症中的免疫功能。 为实现这一目标，我们提出以下具体目标： 具体目标1.为了确定凝集素型氧化低密度脂蛋白受体1在调节PMN-MDSC中的作用， 癌症患者 具体目标2。探讨氧化脂质在PMN-MDSC和DC功能中的作用。

Project Summary Myeloid cells are critical component of tumor microenvironment. Under physiological conditions these cells are comprised of mature terminally differentiated cells: polymorphonuclear neutrophils (PMN) and other granulocytes; macrophages (MΦ); and dendritic cells (DCs). In cancer, myeloid compartment is dramatically affected, which is now considered as one of the major immunological hallmarks of cancer. Tumor-bearing (TB) hosts accumulate immunosuppressive MΦ, DCs in cancer are ineffective in induction of potent immune responses. The prominent change in the myeloid compartment in cancer is the expansion of pathologically activated immature myeloid cells with the potent ability to suppress immune responses – myeloid-derived suppressor cells (MDSC). In TB mice, the total population of MDSC consists of three groups of cells: the most abundant (>75%) immature, pathologically activated neutrophils (PMN-MDSC); less abundant (<20%) population of pathologically activated monocytes - (M-MDSC); and small (<5%) population of early myeloid precursors. The current view considers changes in myeloid cells separately. Different mechanisms applied to the different cells. The gap in our knowledge is how these different myeloid cells can interact with each other in tumor-bearing hosts. In this proposal we will test the hypothesis that oxidized lipids may provide bridge between different populations of myeloid cells in cancer and orchestrate their abnormal function. 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 determine the role of lectin-type oxidized LDL receptor 1 in regulation of PMN-MDSC in cancer patients Specific aim 2. To identify the role of oxidized lipids in the function of PMN-MDSC and DCs.