口腔鳞癌中miR-155调控髓样细胞分化为DC/MDSC的作用机制研究

Dysfunction of DC in the tumor microenvironment is the primary mechanism of tumor immune escape. However, the mechanism of DC dysfunction is unclear. Our studies have confirmed that in the microenvironment of oral squamous cell carcinoma (OSCC), the number of DC decreased while MDSC increased. These results suggested the differentiation of DC is abnormal, and there exists the key molecular which controls the differentiation of DC. Furthermore, we demonstrated the high expression of the miR-155 and the activation of STAT3 in OSCC. The bioinformatics analysis reveals miR-155 can regulate target gene SOCS1, which regulates JAK/STAT3 signaling activation which controls the secretion of inflammatory factors. However, chronic inflammation has proven to be able to control the differentiation of myeloid cells. Therefore, we supposed miR-155 control the differentiation of DC/MDSC and inflammation by regulating SOCS1 expression and JAK/STAT3 signaling activation. This project intends to carry out the following studies: To investigate and explore the impact and mechanism of miR-155 on the DC/MDSC differentiation, function and inflammation; To evaluate and confirm the effect of miR-155/SOCS-1/JAK/STAT3 pathway intervening DC/MDSC and inflammation on tumor. The results can provide the new strategy for the tumor immune therapy.

肿瘤微环境内树突状细胞(DC)功能异常是肿瘤免疫逃逸发生的主要机制，但调控DC分化发育的机制未明。我们证实:口腔鳞癌（OSCC）内起源于髓样细胞的DC数目降低、而髓样起源抑制细胞增加，表明DC分化异常，提示存在调控DC分化异常的关键分子。进一步发现miR-155在OSCC肿瘤组织内高表达，且STAT3在浸润的炎性细胞内高度活化，生物信息学分析显示miR-155可作用于靶基因SOCS1，推测miR-155可通过SOCS1/JAK/STAT3调控DC/MDSC分化且控制炎性因子分泌，而慢性炎症环境内髓样细胞分化异常。因此，项目拟通过细胞及活体动物模型调控OSCC内miR-155表达，观察并探索miR-155调控DC/MDSC分化的作用及分子机制；评价并确定miR-155/SOCS-1/JAK/STAT3通路干预对DC/MDSC分化及炎症影响肿瘤的效果，为肿瘤免疫治疗提供新策略。

本课题组前期研究发现口腔鳞状细胞癌（OSCC）患者外周血内DC比例降低，而MDSC比例升高，猜测DC/MDSC之间分化出现异常；也发现miR-155在组织内表达水平上升；由此，我们推测OSCC微环境内升高的miR-155通过JAK/STAT3通路调控了 DC/MDSC(树突状细胞/髓样起源抑制细胞）分化参与了OSCC进展。因此，我们开展了一下研究：①利用口腔癌移植移植瘤模型、原发舌癌模型分析口腔癌发生过程中髓样细胞尤其是MDSC的变化；②分析口腔癌患者外周血集组织中髓样细胞（单核细胞、DC、MDSC及其亚群的变化并明确其临床意义；③明确miR-155对口腔癌移植瘤模型的作用及对DC/MDSC分化的影响；④明确VEGF通过p-STAT3调控DC/MDSC分化的机制。本研究从动物模型到临床样本，从体内实验到体外实验，发现口腔鳞癌发生过程中髓系细胞亚群（单核细胞、DC、MDSC）分化异常；确定给小鼠饮用4NQ水为建立小鼠原发舌癌模型的最优方法；明确小鼠原发舌癌发生过程中髓系细胞亚群分化出现异常，且MDSC亚群也出现异常；明确口腔鳞癌为环境内miR-155可调控DC／MDSC分化；明确口腔鳞癌微环境内 VEGF可通过活化STAT3调控DC／MDSC分化的机制，这些研究为口腔鳞癌的临床诊断及靶向治疗提供了证据及方法。