The distinct role of cysteinyl leukotriene receptor for myeloid-derived suppressive cells

项目总结 髓系来源的抑制细胞(MDSCs)聚集在血液、淋巴结和 大多数癌症抑制患者和动物的骨髓和肿瘤部位 抗肿瘤免疫，因此是癌症免疫治疗的一个重大障碍。 鉴于MDSCs细胞异质性和可塑性的本质，其机制和 调节和维持MDSC分化和存活的原位条件，以及 MDSC用于促进肿瘤进展的机制在很大程度上仍不清楚。我们的 初步数据表明1型半胱氨基白三烯的重要性 MDSCs聚集和免疫调节活性的受体(CysLTR1) 富含半胱氨酰白三烯(CysLTs)的肿瘤微环境。这些结果导致了 CysLTR1信号在肿瘤诱导的MDSC中起重要作用的新假说 积聚既能抑制免疫，又能促进肿瘤。在这项提案中，我们 将进一步描述肿瘤中MDSCs的表型和功能 微环境，探讨CysLTR1参与的信号转导途径。 同时使用功能增益和功能调节MDSC的分化、周转和功能 丧失功能的方法。我们的研究将为MDSC提供新的见解 诱导和抑制抗肿瘤免疫，以及它们是如何被肿瘤塑造的 微环境，为MDSC靶向治疗提供了一种临床适用的策略 提高目前肿瘤免疫疗法的疗效。

Project summary Myeloid-derived suppressor cells (MDSCs) accumulate in the blood, lymph nodes, and bone marrow and at tumor sites in most patients and animals with cancer suppress antitumor immunity and are therefore a significant impediment to cancer immunotherapy. Given the nature of cellular heterogeneity and plasticity of MDSCs, the mechanisms and in situ conditions that regulate and sustain MDSC differentiation and survival, and the mechanisms MDSC use to promote tumor progression remain largely unknown. Our preliminary data demonstrate the importance of type 1 cysteinyl leukotriene receptor (CysLTR1) for the accumulation and immunoregulatory activity of MDSCs in the cysteinyl leukotrienes (CysLTs)-rich tumor microenvironment. These results have led to the novel hypothesis that CysLTR1 signaling is essential in tumor-induced MDSC accumulation for both immune suppression and tumor promotion. In this proposal, we will characterize further the phenotype and function of MDSCs in the tumor microenvironment, and explore the signaling pathways implicated by CysLTR1 in regulating MDSC differentiation, turnover and function using both gain-of-function and loss-of-function approaches. Our research will provide new insights into how MDSCs are induced and suppress antitumor immunity, and how they are molded by the tumor microenvironment, and may offer a clinically applicable strategy on MDSC targeting to enhance the efficacy of current tumor immunotherapies.