肿瘤细胞中PD-L1表达调控机制的研究进展

Research Progress on Regulation Mechanism of PD-L1 Expression in Cancer Cells

程序性死亡受体-1(programmed death receptor-1,PD-1)锚定在抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)的细胞膜上,其特异性配体程序性死亡–配体1(programmed death-ligand 1,PD-L1)是一种分子量约为40 kDa的I型跨膜蛋白,在正常组织中广泛表达。在正常生理条件下,PD-1和PD-L1之间的胞外结合通过抑制CTLs活性从而阻止自身免疫疾病的发生。然而,PD-L1在黑色素瘤、肺癌、肾细胞癌等恶性肿瘤中的异常上调表达通过促进PD-1/PD-L1介导的CTLs失活导致癌细胞逃避免疫监控。近年来,相关研究分别从基因扩增、染色质修饰、转录与转录后修饰、翻译与翻译后修饰等角度阐述了PD-L1表达调控的分子机制。同时,针对PD-1/PD-L1轴的免疫检查点阻断治疗在多种恶性肿瘤的临床治疗中展现出了较好的疗效。该文系统总结了近年来癌细胞中的PD-L1表达调控机制研究领域的重要成果,并在此基础上展望了针对PD-1/PD-L1轴的肿瘤免疫治疗的应用前景。

Cell surface receptor PD-1(programmed death receptor-1)anchors on the cell membrane of antigen-specific CTLs(cytotoxic T lymphocytes).PD-1 binds to its ligand PD-L1(programmed death-ligand 1),which is a type I transmembrane protein.PD-L1 is widely expressed in normal tissues with a molecular weight of about 40 kDa.Extracellular binding between PD-1 and PD-L1 inhibits the activity of CTLs and prevents autoimmunity under normal physiological conditions.However,the aberrantly upregulated expression of PD-L1 in malignant tumors such as melanoma,lung cancer,and renal cell carcinoma facilitates PD-1/PD-L1-mediated CTLs deactivation and leads to the immune evasion of cancer cells.In recent years,molecular mechanisms that modulating PD-L1 expression from the views of gene amplification,chromatin modification,transcription and post-transcriptional modification,translation and post-translational modification have been unraveled.Meanwhile,immune checkpoint blockade targeting PD-1/PD-L1 axis has exhibited promise in the clinical treatment of a variety of malignancies.In this review,the academic achievements in the regulatory pathways of PD-L1 in cancer cells are summarized,and the perspectives of tumor immunotherapy targeting the PD-1/PD-L1 axis are prospected.