Department of Nephrology, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Medical Microbiology and Parasitology, Fourth Military Medical University, Xi'an, China.
Front Immunol. 2023 Aug 15;14:1226038. doi: 10.3389/fimmu.2023.1226038. eCollection 2023.
Epithelial-mesenchymal transformation (EMT) plays a pivotal role in embryonic development, tissue fibrosis, repair, and tumor invasiveness. Emerging studies have highlighted the close association between EMT and immune checkpoint molecules, particularly programmed cell death ligand 1 (PDL1). PDL1 exerts its influence on EMT through bidirectional regulation. EMT-associated factors, such as YB1, enhance PDL1 expression by directly binding to its promoter. Conversely, PDL1 signaling triggers downstream pathways like PI3K/AKT and MAPK, promoting EMT and facilitating cancer cell migration and invasion. Targeting PDL1 holds promise as a therapeutic strategy for EMT-related diseases, including cancer and fibrosis. Indeed, PDL1 inhibitors, such as pembrolizumab and nivolumab, have shown promising results in clinical trials for various cancers. Recent research has also indicated their potential benefit in fibrosis treatment in reducing fibroblast activation and extracellular matrix deposition, thereby addressing fibrosis. In this review, we examine the multifaceted role of PDL1 in immunomodulation, growth, and fibrosis promotion. We discuss the challenges, mechanisms, and clinical observations related to PDL1, including the limitations of the PD1/PDL1 axis in treatment and PD1-independent intrinsic PDL1 signaling. Our study highlights the dynamic changes in PDL1 expression during the EMT process across various tumor types. Through interplay between PDL1 and EMT, we uncover co-directional alterations, regulatory pathways, and diverse changes resulting from PDL1 intervention in oncology. Additionally, our findings emphasize the dual role of PDL1 in promoting fibrosis and modulating immune responses across multiple diseases, with potential implications for therapeutic approaches. We particularly investigate the therapeutic potential of targeting PDL1 in type II EMT fibrosis: strike balance between fibrosis modulation and immune response regulation. This analysis provides valuable insights into the multifaceted functions of PDL1 and contributes to our understanding of its complex mechanisms and therapeutic implications.
上皮-间充质转化（EMT）在胚胎发育、组织纤维化、修复和肿瘤侵袭中起着关键作用。新的研究强调了 EMT 与免疫检查点分子，特别是程序性细胞死亡配体 1（PDL1）之间的密切关联。PDL1 通过双向调节对 EMT 发挥影响。EMT 相关因子，如 YB1，通过直接结合其启动子增强 PDL1 的表达。相反，PDL1 信号触发下游途径，如 PI3K/AKT 和 MAPK，促进 EMT 并促进癌细胞迁移和侵袭。靶向 PDL1 作为 EMT 相关疾病（包括癌症和纤维化）的治疗策略具有广阔的前景。事实上，PDL1 抑制剂，如 pembrolizumab 和 nivolumab，在各种癌症的临床试验中显示出了有希望的结果。最近的研究还表明，它们在纤维化治疗中具有潜在的益处，可以减少成纤维细胞的激活和细胞外基质的沉积，从而解决纤维化问题。在这篇综述中，我们研究了 PDL1 在免疫调节、生长和纤维化促进中的多方面作用。我们讨论了与 PDL1 相关的挑战、机制和临床观察，包括 PD1/PDL1 轴在治疗中的局限性和 PD1 非依赖性内在 PDL1 信号。我们的研究强调了 PDL1 在各种肿瘤类型 EMT 过程中的表达动态变化。通过 PDL1 与 EMT 的相互作用，我们揭示了共同的方向性改变、调节途径以及 PDL1 干预在肿瘤学中的各种变化。此外，我们的发现强调了 PDL1 在促进纤维化和调节多种疾病中的免疫反应的双重作用，这可能对治疗方法有影响。我们特别研究了靶向 PDL1 在 II 型 EMT 纤维化中的治疗潜力：在纤维化调节和免疫反应调节之间取得平衡。这一分析为 PDL1 的多方面功能提供了有价值的见解，并有助于我们理解其复杂的机制和治疗意义。
