Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Clinical Biochemistry, Mashhad University of Medical Sciences, Mashhad, Iran.
J Cell Physiol. 2020 Oct;235(10):6496-6506. doi: 10.1002/jcp.29671. Epub 2020 Apr 2.
Tumor evasion from the host immune system is a substantial strategy for tumor development and survival. The expression of many immune checkpoint proteins in cancer cells is a mechanism by which tumor cells escape from the immune system. Among the well-known immune checkpoints that can tremendously affect tumor development and cancer therapy are the programmed death-ligand-1/programmed death-1 (PD-L1/PD-1). To tackle this phenomenon and improve the therapeutic strategies in cancer treatment, the blockade of the PD-L1/PD-1 pathway is introduced as a target, but the therapeutic advantage of PD L1/PD-1 blockade has not fulfilled the expectations. This condition may be associated with a different type of resistance in a considerable number of patients. A crucial issue to conquer resistance against immune checkpoint blockade therapy is to understand how PD-L1 level is regulated. However, the mechanisms by which the PD-L1 expression is regulated are complicated, and they can occur at different levels from signaling pathways to posttranscriptional levels. For example, various transcriptional factors, such as hypoxia-inducible factor-1, nuclear factor-κΒ, interferon-γ, STAT3, MYC, and AP-1 can regulate the PD-L1 distribution at the transcriptional level. Herein, we tried to focus on the most important regulatory mechanisms of PD-L1 by inducible agents in the tumor cells, such as signaling pathways, transcriptional factors, and posttranscriptional factors. Finally, these approaches may open up new windows for targeting tumor immune evasion and suggest the novel suppressors of PD-L1 for efficient therapeutics.
肿瘤逃避宿主免疫系统是肿瘤发展和生存的重要策略。癌细胞中许多免疫检查点蛋白的表达是肿瘤细胞逃避免疫系统的一种机制。在许多能够极大地影响肿瘤发展和癌症治疗的著名免疫检查点中，程序性死亡配体-1/程序性死亡受体-1（PD-L1/PD-1）是最受关注的。为了解决这一现象并改进癌症治疗中的治疗策略，引入了阻断 PD-L1/PD-1 途径作为靶点，但 PD L1/PD-1 阻断的治疗优势并未达到预期。这种情况可能与相当数量的患者中存在不同类型的耐药性有关。克服免疫检查点阻断治疗耐药性的一个关键问题是了解 PD-L1 水平是如何调节的。然而，PD-L1 表达调控的机制很复杂，它们可以发生在从信号通路到转录后水平的不同水平上。例如，各种转录因子，如缺氧诱导因子-1、核因子-κB、干扰素-γ、STAT3、MYC 和 AP-1 可以在转录水平上调节 PD-L1 的分布。在此，我们试图关注肿瘤细胞中诱导剂对 PD-L1 的最重要调控机制，如信号通路、转录因子和转录后因子。最后，这些方法可能为靶向肿瘤免疫逃逸开辟新的窗口，并为有效的治疗提供新的 PD-L1 抑制剂。
