School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.
Department of Neurobiology, School of Medicine, South China University of Technology, Guangzhou, China.
Clin Exp Pharmacol Physiol. 2022 Dec;49(12):1281-1293. doi: 10.1111/1440-1681.13717. Epub 2022 Sep 15.
Programmed death ligand 1 (PD-L1) is widely known as an immune checkpoint, and immunotherapy through the inhibition of checkpoint molecules has become an important component in the successful treatment of tumours via programmed death 1 (PD-1)/PD-L1 signalling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) are elusive. We previously found that PD-L1 can bind to PD-L1 and cause cell detachment. However, the detailed molecular mechanisms of how PD-L1 binds to PD-L1 and how it transmits signals to the cell remain unclear. In this study, we disclosed that PD-L1 expression was dramatically upregulated in CRC compared to normal tissues. Ectopic expression of PD-L1 inhibits cell adhesive capacity and promotes cell migration in CRC cell lines, while silencing PD-L1 had the opposite effects and suppressed invasion and proliferation. Mechanistically, PD-L1 was found to promote epithelial-mesenchymal transition (EMT) through the ERK signalling molecule pathway and interacted with the 1-86 aa fragment of KRAS to transduce signals. Collectively, our study demonstrated the role of PD-L1 after binding to PD-L1 in CRC, thereby providing a new theoretical basis for further improving immunotherapy with anti-PD-L1 antibodies.
程序性死亡配体 1（PD-L1）是众所周知的免疫检查点，通过抑制检查点分子的免疫疗法已成为通过程序性死亡 1（PD-1）/PD-L1 信号通路成功治疗肿瘤的重要组成部分。然而，其在结直肠癌（CRC）中的生物学功能和表达谱仍难以捉摸。我们之前发现 PD-L1 可以与 PD-L1 结合并导致细胞脱落。然而，PD-L1 如何与 PD-L1 结合以及如何将信号传递到细胞的详细分子机制仍不清楚。在这项研究中，我们揭示了 PD-L1 在 CRC 中的表达明显高于正常组织。CRC 细胞系中 PD-L1 的异位表达抑制细胞黏附能力并促进细胞迁移，而沉默 PD-L1 则产生相反的效果，抑制侵袭和增殖。从机制上讲，发现 PD-L1 通过 ERK 信号分子途径促进上皮-间充质转化（EMT），并与 KRAS 的 1-86 aa 片段相互作用以传递信号。总之，我们的研究表明 PD-L1 与 PD-L1 结合后在 CRC 中的作用，从而为进一步提高抗 PD-L1 抗体的免疫疗法提供了新的理论依据。
