ERAdP在肝癌肿瘤浸润淋巴细胞负向调控肝癌干细胞自我更新中的作用及机制研究

Whether liver cancer infiltrating lymphocytes (TILs) in the microenvironment are involved in the regulation of liver cancer stem cells self-renewal remains unclear. The preliminary results demonstrated that liver cancer TILs can suppress the proliferation, migration and proliferation of liver tumor sphere. The results of cDNA microarray and tumor samples detection showed that the expression of ERAdP in TIL cells of recurrent hepatocellular carcinoma patients is significantly lower than that of TIL cells of patients no relapse. Liver cancer TILs over-expressing ERAdP inhibit the formation of liver tumor sphere significantly. Combining with the publication of applicant, ERAdP can activate cytokine secretion in natural immune system, we hypothesized that the endoplasmic reticulum protein ERAdP in liver cancer TILs plays an important role in inhibiting liver cancer stem cell self-renewal. To verify this hypothesis, we will explore that how ERAdP protein regulating cytokine secretion to inhibit liver cancer CSC self-renewal, and the molecular mechanism. The project is armed to deepen the understanding of the regulation of liver cancer TILs in liver cancer stem cells self-renewal, in order to establish a new subtype of TILs for the treatment of liver cancer, and to provide new targets for liver cancer TILs activation.

肝癌组织微环境中的肿瘤浸润淋巴细胞（TILs）参与调控肝癌干细胞自我更新的作用尚未有明确报道。前期研究结果表明，肝癌TILs可以有效抑制肝癌细胞的增殖、迁移与干细胞肿瘤球增殖。cDNA表达谱芯片及肿瘤样本检测显示，复发性肝癌患者TILs中的ERAdP表达量明显低于未复发肝癌患者TILs中的表达量,肝癌TILs高表达ERAdP可以显著抑制肝癌干细胞球形成。结合2015年申请人发表的研究成果，ERAdP在天然免疫系统中具有活化细胞因子分泌的功能，我们推测“内质网接头蛋白ERAdP在TILs抑制肝癌干细胞自我更新中具有重要作用”。为此，本项目将从TILs微环境角度,深入探讨ERAdP蛋白调控分泌的细胞因子，如何抑制肝癌CSC自我更新及分子机制。旨在加深对肝癌TILs参与调控肝癌干细胞自我更新的认识，以期为肝癌TILs治疗建立新的亚群分型，筛选新的肝癌TILs活化靶点。

丝氨酸/苏氨酸激酶AURKA参与细胞有丝分裂，介导了肿瘤细胞的增殖、转移和耐药。然而，AURKA是否参与肿瘤免疫调节目前尚不清楚。因此，本项目探讨了AURKA在三阴乳腺癌(TNBC)免疫调节中的作用。我们的研究表明，敲降TNBC细胞中的AURKA可激活CD8+ T细胞的活性和细胞增殖从而增加对肿瘤细胞的免疫应答。机制研究表明，细胞核定位的AURKA通过MYC途径促进PD-L1表达。小分子药物和基因上阻断MYC可抑制PD-L1的表达。此外，动物实验表明，AURKA下调能够增强肿瘤组织中浸润的CD8+ T细胞活性。综上所述，我们的研究结果阐明，核定位AURKA在TNBC免疫逃逸中的关键作用，为靶向核AURKA，恢复免疫细胞对TNBC的免疫应答提供了基础。