Li Zhen, Wang Fengdi, Dang Jianzhong, Cheng Fanjun, Zheng Fang
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, China.
Transl Cancer Res. 2022 Oct;11(10):3698-3710. doi: 10.21037/tcr-22-292.
Transforming growth factor-β1 (TGF-β1) is the predominant form of TGF-β and induces epithelial-to-mesenchymal transition (EMT) in melanoma. Tumor cell-intrinsic programmed death ligand-1 (PD-L1) plays a crucial role in maintenance of the EMT in melanoma. However, the relationship among tumor cell-intrinsic PD-L1, TGF-β1 and EMT is very complicated.
We investigated the bidirectional regulation between cell-intrinsic PD-L1 and TGF-β1 in melanoma, and explored the role of PD-L1 in TGF-β1-induced EMT and tumor progression.
We found that TGF-β1 upregulated PD-L1 expression in B16-F0 and B16-F10 melanoma cells. Interestingly, PD-L1 also enhanced the intracellular TGF-β1 mRNA levels and induced the secretion of TGF-β1. Immunohistochemical staining revealed that PD-L1 protein expression was co-localized with α-smooth muscle actin (SMA) protein expression in melanoma, suggesting that PD-L1 was associated with EMT. By using shRNA lentivirus to knockdown PD-L1 (PD-L1-shRNA) in melanoma cell lines, we showed that TGF-β1-induced EMT was significantly inhibited in PD-L1-shRNA melanoma cells, which was characterized by the lower fibronectin (FN1) mRNA and higher E-cadherin (CDH1) mRNA levels (both are EMT markers) than that in control. TGF-β1-induced melanoma cell proliferation and migration were also markedly inhibited in PD-L1-shRNA cells. Consistent with the observation in vitro, PD-L1 knockdown inhibited tumor growth and repressed TGF-β1-induced EMT characterized by reduction of FN1 and increase of CDH1 in mouse model.
The present study demonstrated a bidirectional regulation between cell-intrinsic PD-L1 and TGF-β1 in melanoma, which may help in designing promising combinations which include targeting TGF-β1 signaling along with PD-L1.
转化生长因子-β1（TGF-β1）是TGF-β的主要形式，可诱导黑色素瘤发生上皮-间质转化（EMT）。肿瘤细胞内源性程序性死亡配体-1（PD-L1）在黑色素瘤EMT的维持中起关键作用。然而，肿瘤细胞内源性PD-L1、TGF-β1与EMT之间的关系非常复杂。
我们研究了黑色素瘤中细胞内源性PD-L1与TGF-β1之间的双向调节，并探讨了PD-L1在TGF-β1诱导的EMT和肿瘤进展中的作用。
我们发现TGF-β1上调了B16-F0和B16-F10黑色素瘤细胞中PD-L1的表达。有趣的是，PD-L1还提高了细胞内TGF-β1 mRNA水平并诱导了TGF-β1的分泌。免疫组织化学染色显示，黑色素瘤中PD-L1蛋白表达与α-平滑肌肌动蛋白（SMA）蛋白表达共定位，表明PD-L1与EMT相关。通过使用shRNA慢病毒敲低黑色素瘤细胞系中的PD-L1（PD-L1-shRNA），我们发现TGF-β1诱导的EMT在PD-L1-shRNA黑色素瘤细胞中受到显著抑制，其特征是纤连蛋白（FN1）mRNA水平较低，而E-钙黏蛋白（CDH1）mRNA水平较高（两者均为EMT标志物），均低于对照组。TGF-β1诱导的黑色素瘤细胞增殖和迁移在PD-L1-shRNA细胞中也受到明显抑制。与体外观察结果一致，在小鼠模型中，敲低PD-L1可抑制肿瘤生长，并抑制以FN1减少和CDH1增加为特征的TGF-β1诱导的EMT。
本研究证明了黑色素瘤中细胞内源性PD-L1与TGF-β1之间的双向调节，这可能有助于设计出有前景的联合治疗方案，包括靶向TGF-β1信号通路和PD-L1。
