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

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；signal transduction pathway）; 3) To study the effect of dopamine on tumor growth through inhibiting MDSC. Successful completion of these studies will result in a better understanding of the mechanisms of action by dopamine and immune tolerance, which may lead to the discovery of novel targets for the intervention in tumor-associated immunosuppression.

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。

髓源性抑制细胞（MDSCs）是引起肿瘤免疫抑制及阻碍抗肿瘤免疫治疗效应的主要原因之一，能有效抑制其功能的措施有望于显著增强抗肿瘤治疗效果。神经递质多巴胺被发现具有抗肿瘤活性，但机制如何尚未阐明。本课题针对神经递质多巴胺的抗肿瘤活性，研究多巴胺对MDSC功能的抑制作用及可能机制，探讨多巴胺抑制MDSC与其抗瘤作用间的关系。通过本课题的研究，我们证明多巴胺可显著降低荷瘤鼠Gr-1+CD115+单核细胞性MDSC的免疫抑制功能，从而延缓肿瘤生长；多巴胺主要作用于MDSC表面D1样多巴胺受体抑制MDSC NO的产生，从而减轻MDSC对T细胞的抑制作用，促进效应性CD4+与CD8+T细胞功能，其中多巴胺对ERK、JNK信号通路活化的下调在降低NO产生过程中发挥重要作用；此外，多巴胺还可一定程度地促进MDSC的分化成熟。综上，多巴胺通过调节Gr-1+CD115+单核细胞性MDSC的功能改善肿瘤的免疫抑制状态、提高机体抗肿瘤免疫能力。本研究揭示了神经递质多巴胺抑制肿瘤单核细胞性MDSC的新功能，有助于更好地理解疾病过程中神经-免疫系统的相互作用，为今后利用多巴胺或其D1样受体激动剂克服肿瘤诱导的免疫抑制、探寻更加有效的肿瘤治疗策略奠定基础。