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

项目摘要 骨髓源性抑制细胞（MDSC）在血液、淋巴结和淋巴结中积累， 在大多数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重要障碍。 鉴于MDSC的细胞异质性和可塑性的性质， 调节和维持MDSC分化和存活的原位条件， MDSC用于促进肿瘤进展的机制在很大程度上仍然未知。我们 初步数据表明1型半胱氨酰白三烯的重要性 受体（CysLTR1）的积累和MDSC的免疫调节活性， 半胱氨酰白三烯（CysLTs）丰富的肿瘤微环境。这些结果导致 CysLTR 1信号传导在肿瘤诱导MDSC中是必需的新假设 用于免疫抑制和肿瘤促进的累积。在本提案中，我们 将进一步表征MDSC在肿瘤中的表型和功能 微环境，并探索CysLTR1参与的信号通路， 调节MDSC分化，周转和功能，使用功能获得和 功能丧失的方法。我们的研究将提供新的见解，MDSC是如何 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，并可能提供一个临床适用的策略MDSC靶向， 增强当前肿瘤免疫疗法的功效。

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.