A20在肿瘤来源髓系抑制细胞中高表达的机理研究

Myeloid-derived suppressor cells (MDSCs), a group of immunosuppressive cells composed by immature Dendritic cells, macrophages and other myeloid cells, fosters proliferation and migration of cancer. A20 protein is a key negatively regulator in NF-κB signal pathway, which can regulate immune responses by inhibiting maturation and activation of immune cells such as DCs and T cells. In previous studies, we observed high expression of A20 in myeloid-derived suppressor cells (MDSCs) of tumor microenvironment in human lung cancer and mouse model. However, the mechanism by which A20 is regulated in MDSCs of tumor microenvironment and the function of A20 in MDSCs remains to be demonstrated. In the recent study,we demonstrated that overexpression of A20 in MDSCs reduced the spontaneous apoptosis of these cells and promoted tumor growth. Subsequently,we found that Adiponectin, PS and TNF-α, which constantly induced the expression of A20 through GSK3β , was accumulated in the tumor microenvironment. In the present study, by using RNA-Seq and Luminex liquid microarrays and other metheod,we will have a deep investigation on potential molecular mechanisms of A20 expression in clinical sample and mouse lung cancer model.Our study aim to provide theory basis and new option in TME-targeted cancer biotherapy.

髓系抑制细胞（MDSCs）由未成熟的树突状细胞（DCs）、巨噬细胞和粒细胞等髓系细胞构成，具有抑制免疫、促进肿瘤生长和转移的作用。A20是NF-κB信号通路关键的负调控因子，通过抑制DCs和T细胞等免疫细胞的成熟或激活调节免疫反应。 申请人前期在肺癌临床标本和小鼠肿瘤模型中发现，A20在肿瘤来源MDSCs中呈高表达。但是，A20在MDSCs中表达的机制及其功能尚不明确。申请人近期研究证实，A20高表达减少MDSCs自发凋亡，促进肿瘤生长；随后发现脂联素（Adiponectin）、磷酯酰丝氨酸（PS）和TNF-α等分子在肿瘤微环境中大量积累，并通过GSK3β诱导MDSCs中A20的表达。基于临床标本和多种小鼠模型，运用RNA-Seq检测和液相芯片等技术手段，本项目拟深入研究肿瘤调控MDSCs中A20表达的分子机制，阐明A20在该细胞中的功能，为靶向MDSCs的肿瘤治疗提供依据和新思路。

髓系抑制细胞（MDSC）是肿瘤免疫微环境的重要组成成分，具有抑制免疫、促进肿瘤生长和转移的作用。A20是NF-κB和MAPK等信号通路关键的负调控因子，具有重要的免疫调控功能。本课题以A20为切入点，按照原定计划实施，课题进展顺利。研究发现：1.A20在肿瘤来源的免疫细胞中高表达，并且与肿瘤分级和预后相关；2.肿瘤微环境中的脂联素、磷酯酰丝氨酸（PS）和cGAMP等能够诱导A20的表达，同时人体自然代谢产物γ-氨基丁酸（GABA）也能够诱导间充干细胞和巨噬细胞中A20的表达；3.用si-RNA下调A20表达，能够显著抑制肿瘤的生长，促使肿瘤免疫微环境由免疫抑制状态向免疫激活状态转变；4.相比其他组织来源的MDSC，肿瘤来源的MDSC中MAPK信号通路高度活化；体外用MAPK信号通路特异性抑制剂能够显著诱导MDSC的凋亡；体内给予荷瘤小鼠一定剂量的MAPK信号通路特异性抑制剂能够显著抑制肿瘤的生长并激活免疫反应。综合上述一系列研究，本课题的实施具有重要的临床意义和应用前景，将指导针对A20或MDSC的相关肿瘤靶向治疗；同时新的A20的诱导分子的发现和调控机制的阐述，也为肿瘤靶向治疗提供了新的靶点分子。. 课题共标注发表SCI论文5篇，最高影响因子为7.36（cancer letters），累计影响因子25.29。在此期间，课题负责人获得国家自然科学基金面上项目资助和省科技厅重点项目。参与课题研究生有2名博士毕业（其中一名进入博士后工作站，并申请到博士后面上一等资助和特别资助）。培养一名硕士研究生，目前已经顺利完成硕士课题并发表文章。