School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia; School of Engineering, Macquarie University, Sydney 2109, Australia.
School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
Biochim Biophys Acta Mol Cell Res. 2019 Dec;1866(12):118526. doi: 10.1016/j.bbamcr.2019.118526. Epub 2019 Aug 6.
Expression of programmed death-ligand 1 (PD-L1) in cancer cells plays an important role in cancer-immune cell interaction. The emerging evidence suggests regulation of PD-L1 expression by several tumor microenvironmental cues. However, the association of PD-L1 expression with chemical and mechanical features of the tumor microenvironment, specifically epidermal growth factor receptor (EGFR) signaling and matrix stiffness, remains elusive. Herein, we determine whether EGFR targeting and substrate stiffness affect the regulation of PD-L1 expression. Breast carcinoma cell lines, MCF7 and MDA-MB-231, were cultured under different conditions targeting EGFR and exposing cells to distinct substrate stiffness to evaluate PD-L1 expression. Furthermore, the ability to form aggregates in short-term culture of breast carcinoma cells and its effect on expression level of PD-L1 was probed. Our results indicated that PD-L1 expression was altered in response to both EGFR inhibition and substrate stiffness. Additionally, a positive association between the formation of multicellular aggregates and PD-L1 expression was observed. MDA-MB-231 cells expressed the highest PD-L1 level on a stiff substrate, while inhibition of EGFR reduced expression of PD-L1. The results suggested that both physical and chemical features of tumor microenvironment regulate PD-L1 expression through alteration of tumor aggregate formation potential. In line with these results, the in-silico study highlighted a positive correlation between PD-L1 expression, EGFR signaling, epithelial to mesenchymal transition related transcription factors (EMT-TFs) and stemness markers in metastatic breast cancer. These findings improve our understanding of regulation of PD-L1 expression by tumor microenvironment leading to evasion of tumor cells from the immune system.
癌细胞程序性死亡配体 1（PD-L1）的表达在癌症-免疫细胞相互作用中起着重要作用。新出现的证据表明，PD-L1 的表达受多种肿瘤微环境线索的调节。然而，PD-L1 的表达与肿瘤微环境的化学和机械特征（特别是表皮生长因子受体（EGFR）信号和基质硬度）之间的关联仍然难以捉摸。在此，我们确定 EGFR 靶向和基质硬度是否会影响 PD-L1 表达的调节。培养 MCF7 和 MDA-MB-231 乳腺癌细胞系，通过针对 EGFR 的不同条件和使细胞暴露于不同的基质硬度来评估 PD-L1 表达。此外，还探讨了乳腺癌细胞短期培养中形成聚集体的能力及其对 PD-L1 表达水平的影响。结果表明，PD-L1 的表达会响应 EGFR 抑制和基质硬度而改变。此外，还观察到多细胞聚集体的形成与 PD-L1 表达之间存在正相关。MDA-MB-231 细胞在硬基质上表达最高水平的 PD-L1，而 EGFR 抑制则降低了 PD-L1 的表达。结果表明，肿瘤微环境的物理和化学特征通过改变肿瘤聚集体形成潜力来调节 PD-L1 的表达。与这些结果一致，计算机模拟研究突出了转移性乳腺癌中 PD-L1 表达、EGFR 信号、上皮间质转化相关转录因子（EMT-TFs）和干性标志物之间的正相关性。这些发现提高了我们对肿瘤微环境调节 PD-L1 表达的理解，从而导致肿瘤细胞逃避免疫系统的攻击。
