多巴胺“解除”肿瘤MDSC抑制作用的新功能及其对肿瘤生长的影响

项目名称： 多巴胺“解除”肿瘤MDSC抑制作用的新功能及其对肿瘤生长的影响

项目编号： No.81201602

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 吴瑾

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 近来认为：髓系来源抑制细胞（MDSC）是引起肿瘤免疫抑制的主要原因。MDSC通过抑制T细胞功能等机制参与免疫逃逸，如何消除其功能以增强抗肿瘤效果是肿瘤免疫研究的热点。文献报道多巴胺具有抗肿瘤活性，机制如何尚未阐明。我们前期研究发现：体外经多巴胺处理后，肿瘤诱导的MDSC对T细胞增殖的抑制作用明显降低；肺癌荷瘤小鼠体内注射多巴胺，同样使小鼠MDSC几乎失去对T细胞增殖的抑制能力；瘤体明显缩小。提示：多巴胺可抑制MDSC功能，具体机制有待深入研究。 本项目拟通过纯化的MDSC和小鼠肿瘤模型，从分子、细胞及动物水平进一步探讨多巴胺如何解除MDSC抑制特性(抑制性因子；分化成熟；迁移性等)、可能的分子机制（受体；信号通路）以及其通过抑制MDSC对肿瘤生长的影响，从而明确多巴胺解除MDSC功能、抑制肿瘤生长的作用及机制。本研究通过揭示多巴胺的新功能为消除肿瘤免疫抑制、寻找肿瘤治疗的新靶点奠定基础。

中文关键词： 髓源性抑制细胞；神经递质；免疫抑制；一氧化氮；肿瘤

英文摘要： A growing body of evidence suggests that host immune cells with a suppressive phenotype pose a significant hurdle to successful immune enhancing therapy for cancer. MDSCs (myeloid-derived suppressor cell) are now considered the major factors responsible for the immunosuppressive status of cancer. They play an important role in tumor escape mainly by suppressing T-cell responses. Intensive studies in recent years are focused on the identification of the therapeutic means to eliminate MDSC-mediated immune suppression, thereby will improve the efficacy of immune-based therapies. It was reported that neurotransmitter dopamine has anti-tumor activities, but the detailed mechanisms remain elusive. Our preliminary data showed that dopamine could eliminate inhibitory effects of Tumor-induced MDSC on T cell proliferation both in vitro and in vivo, which suggested that dopamine could inhibit the function of MDSC, but the related mechanisms need to be elucidated. By the use of purified MDSC and mouse model, three specific aims will be pursued in this study: 1) To study what kinds of inhibitory characteristics of MDSC are suppressed by dopamine(iNOS、ARGI；inhibitory cytokines；differentiation；migration ability); 2) To study the underlying mechanisms that are involved in the function of dopamine posing on MDSC（receptors：D1/D2

英文关键词： Myeloid-derived suppressor cell；neurotransmitter；immune suppression；nitric oxide；cancer