Bidirectional regulation between tumor cell-intrinsic PD-L1 and TGF-β1 in epithelial-to-mesenchymal transition in melanoma.
Bidirectional regulation between tumor cell-intrinsic PD-L1 and TGF-β1 in epithelial-to-mesenchymal transition in melanoma.
复制标题
DOI：
10.21037/tcr-22-292
复制
发表时间：
2022-10
影响因子：
0.9
通讯作者：
中科院分区：
文献类型：
--
作者：
转化生长因子-β1（Transforming growth factor-β1，TGF-β1）是TGF-β的主要形式，在黑色素瘤中诱导上皮细胞向间质细胞转化（epithelial-to-mesenchymal transition，EMT）。肿瘤细胞内源性程序性死亡配体-1（PD-L1）在维持黑色素瘤EMT中起着至关重要的作用。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和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B16-F0和B16-F10黑色素瘤细胞中PD-L1的表达。有趣的是，PD-L1还增强细胞内TGF-β1 mRNA水平并诱导TGF-β1分泌。免疫组织化学染色显示PD-L1蛋白表达与α-平滑肌肌动蛋白（SMA）蛋白表达在黑色素瘤中共定位，提示PD-L1与EMT相关。利用shRNA慢病毒技术敲低黑色素瘤细胞系中PD-L1（PD-L1-shRNA），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，表现为EMT标志物纤维连接蛋白（FN 1）mRNA水平较对照组降低，E-钙粘蛋白（CDH 1）mRNA水平较对照组升高。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，PD-L1敲低抑制了小鼠模型中的肿瘤生长并抑制了TGF-β1诱导的EMT，其特征在于FN 1减少和CDH 1增加。本研究证明了黑色素瘤中细胞内源性PD-L1和TGF-β1之间的双向调节，这可能有助于设计有前景的组合，包括靶向TGF-β1信号转导沿着PD-L1。
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.