髓系抑制性细胞通过miR-181b介导甲状腺乳头状癌免疫逃逸的机制研究

Myeloid-derived Suppressor Cells (MDSC) promote immune escape in tumor occurrence and development by inhibiting T cell activation. Our preliminary data determined that MDSC (CD11b+CD14-CD33+) were significantly increased in patients with papillary thyroid carcinoma (PTC.), and showed that MDSC from patients inhibited CD4+ T cell proliferation. Further study found that the expression of miR-181b an PD-L1were significantly increased in MDSC of the patient with PTC, which might be involved in the development and invasion of PTC through promoting immune escape. We hypothesized that miR-181b may down regulate immune response through ATK signal pathways by target on PTEN, and then increased the activity of mTOR and raised the level of PD-L1. In this project, we will use in vitro and in vivo experiments to study the roles of miR-181b upregulated in MDSC in PTC immune escape and the underlining mechanisms. By combining with clinical data, we are trying to verify that MDSC down regulate immune response through the expression of PD-L1 regulated by miR-181b, providing new treatment targets for PTC.

髓系抑制性细胞(MDSC)通过抑制T细胞促进肿瘤免疫逃逸，导致肿瘤的发生发展。我们前期研究发现甲状腺乳头状癌(PTC)患者MDSC (CD11b+CD14-CD33+)比例明显升高，MDSC显著抑制CD4+T细胞增殖。进一步研究发现miR-181b 和PD-L1在PTC患者的MDSC中表达明显升高。我们推测miR-181b可能靶向作用于PTEN，通过ATK通路增加mTOR的信号活性而上调MDSC中PD-L1的水平，在MDSC介导的肿瘤免疫逃逸中扮演重要角色。本研究拟采用细胞模型、动物模型及分子生物学实验探明MDSC中表达升高的miR-181b通过PTEN-ATK-mTOR-PD-L1通路调控T细胞的作用；与临床样本数据相结合，进一步验证 MDSC通过miR-181b调控PD-L1的表达对T细胞的负调控作用，为PTC的免疫治疗提供新方向及手段。

髓系抑制性细胞（MDSC）通过抑制T细胞促进肿瘤免疫逃逸，导致肿瘤的发生发展。本项目探讨循环血中MDSCs参与甲状腺乳头状癌（PTC）的免疫逃逸机制，我们研究发现PTC患者外周血中PMN-MDSC含量显著增高，通过与PTC细胞株共培养，发现PMN-MDSC能促进PTC细胞体外和体内迁移能力。通过共培养后的细胞系进行mRNA表达谱和miRNA表达谱检测，我们发现miR-486-3p可能在PMN-MDSC促瘤作用中发挥重要调节功能，通过体外实验证实PMN-MDSC通过调节miR-486-3p/NF-κB2轴促进甲状腺乳头状癌细胞的迁移与侵袭。该部分研究为PTC的免疫治疗提供新方向及手段。随着我们对MicroRNA(MiRNA)与PTC研究的深入，我们进一步揭示了现miR-3619-3p在PTC中的作用机制。研究结果发现miR-3619-3p在PTC组织及细胞株中表达水平增高，其高表达与肿瘤的被膜侵犯、多灶性及淋巴结转移特性相关。miR-3619-3p可能通过稳定β-catenin的mRNA而激活wnt/β-catenin通路，从而促进PTC细胞迁移侵袭。该研究为探索甲状腺癌的发生发展机制及免疫治疗提供新的方向及理论依据。.我们同时探讨药物A对糖代谢和脂代谢的影响及其作用机制，通过动物实验我们发现药物A可能减轻ob小鼠脂代谢蓄积，并且改善脂代谢蓄积造成的肝脏损伤。对给药组和对照组小鼠肝脏进行高通量测序，筛选出差异表达的miRNA和mRNA，分析结果发现差异表达的mRNA大多与脂代谢相关信号通路相关如非游离脂肪酸的合成、脂肪酸的代谢和PPAR信号通路，以上结果均提示药物A在小鼠脂代谢中发挥着重要作用。