Upregulation of PD-L1 expression in breast cancer cells through the formation of 3D multicellular cancer aggregates under different chemical and mechanical conditions
Upregulation of PD-L1 expression in breast cancer cells through the formation of 3D multicellular cancer aggregates under different chemical and mechanical conditions
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DOI：
10.1016/j.bbamcr.2019.118526
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发表时间：
2019-12-01
影响因子：
5.1
通讯作者：
Warkiani, Majid Ebrahimi
中科院分区：
文献类型：
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作者：
Azadi, Shohreh;Es, Hamidreza Aboulkheyr;Warkiani, Majid Ebrahimi
程序性死亡配体1（PD-L1）在癌细胞中的表达在癌症-免疫细胞相互作用中起重要作用。新出现的证据表明，PD-L1表达受几种肿瘤微环境因素的调节。然而，PD-L1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）信号传导和基质硬度）的关联仍然难以捉摸。在此，我们确定EGFR靶向和底物硬度是否影响PD-L1表达的调节。在靶向EGFR的不同条件下培养乳腺癌细胞系MCF 7和MDA-MB-231，并将细胞暴露于不同的底物硬度，以评价PD-L1表达。此外，探索了在乳腺癌细胞的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。我们的研究结果表明，PD-L1的表达在EGFR抑制和底物硬度的反应中发生了变化。此外，观察到多细胞聚集体的形成与PD-L1表达之间存在正相关性。MDA-MB-231细胞在刚性基质上表达最高水平的PD-L1，而EGFR的抑制降低了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表达。与这些结果一致，计算机模拟研究强调了转移性乳腺癌中PD-L1表达、EGFR信号传导、上皮间质转化相关转录因子（EMT-TF）和干细胞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，导致肿瘤细胞逃避免疫系统。
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 sternness 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.