miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint.
miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint.
复制标题
miR-424(322)通过阻断PD-L1免疫检查点激活T细胞免疫反应来逆转化疗耐药
DOI：
10.1038/ncomms11406
复制
发表时间：
2016-05-05
影响因子：
16.6
通讯作者：
Chen K
中科院分区：
文献类型：
--
作者：
Xu S;Tao Z;Hai B;Liang H;Shi Y;Wang T;Song W;Chen Y;OuYang J;Chen J;Kong F;Dong Y;Jiang SW;Li W;Wang P;Yuan Z;Wan X;Wang C;Li W;Zhang X;Chen K
抑制性免疫受体PD-L1、PD-1和CTLA-4的免疫检查点阻断已成为几种晚期癌症的成功治疗策略。在这里，我们证明了miR-424（322）调节化疗耐药卵巢癌中的PD-L1/PD-1和CD 80/CTLA-4通路。miR-424（322）与PD-L1、PD-1、CD 80和CTLA-4表达呈负相关。肿瘤中高水平的miR-424（322）与卵巢癌患者的无进展生存率呈正相关。机制研究表明，miR-424（322）通过直接结合3′-非翻译区抑制PD-L1和CD 80表达。miR-424（322）表达的恢复逆转了化疗耐药性，这伴随着PD-L1免疫检查点的阻断。化疗和免疫治疗的协同作用与功能性细胞毒性CD 8 + T细胞的增殖以及骨髓源性抑制性细胞和调节性T细胞的抑制有关。总的来说，我们的数据表明PD-L1和化疗耐药性之间通过microRNA调控级联反应存在生物学和功能相互作用。
Immune checkpoint blockade of the inhibitory immune receptors PD-L1, PD-1 and CTLA-4 has emerged as a successful treatment strategy for several advanced cancers. Here we demonstrate that miR-424(322) regulates the PD-L1/PD-1 and CD80/CTLA-4 pathways in chemoresistant ovarian cancer. miR-424(322) is inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. High levels of miR-424(322) in the tumours are positively correlated with the progression-free survival of ovarian cancer patients. Mechanistic investigations demonstrated that miR-424(322) inhibited PD-L1 and CD80 expression through direct binding to the 3′-untranslated region. Restoration of miR-424(322) expression reverses chemoresistance, which is accompanied by blockage of the PD-L1 immune checkpoint. The synergistic effect of chemotherapy and immunotherapy is associated with the proliferation of functional cytotoxic CD8+ T cells and the inhibition of myeloid-derived suppressive cells and regulatory T cells. Collectively, our data suggest a biological and functional interaction between PD-L1 and chemoresistance through the microRNA regulatory cascade.