下调和上调
长春瑞滨
癌症研究
医学
肺癌
组织微阵列
表皮生长因子受体
基因敲除
免疫疗法
PD-L1
癌症
细胞凋亡
免疫组织化学
病理
内科学
顺铂
生物
化疗
生物化学
基因
作者
Kenichi Suda,Leslie Rozeboom,Christopher J. Rivard,Hui Yu,Kim Ellison,Mary Ann Melnick,Trista K. Hinz,Daniel C. Chan,Lynn E. Heasley,Katerina Politi,Tetsuya Mitsudomi,Fred R. Hirsch
出处
期刊:Lung Cancer
[Elsevier]
日期:2017-07-01
卷期号:109: 1-8
被引量:26
标识
DOI:10.1016/j.lungcan.2017.04.010
摘要
Immunotherapy that targets the programmed death-1/programmed death-ligand 1 (PD-L1) axis has been approved for treatment of non-small cell lung cancer (NSCLC) patients in many countries. However, our current understanding of the role of immunotherapies on NSCLC patients with epidermal growth factor receptor (EGFR) mutation, following acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs), is so far unclear. Especially, there is little data on if each acquired resistance mechanism to EGFR-TKIs alters PD-L1 expression status which is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents.Lung cancer cell lines (HCC827, HCC4006, PC9, H1975, H358, SW900, and H647) and their daughter cells that acquired resistance to EGFR-TKIs or cytotoxic drugs (cisplatin or vinorelbine) were examined. PD-L1 expression was analyzed by immunohistochemistry, immunoblotting, and/or fluorescent imaging. Published microarray data were also employed to evaluate our findings.We found correlations between therapy-induced E-cadherin downregulation and decreased PD-L1 expression using our cell lines and published microarray data. ShRNA mediated E-cadherin knockdown decreased PD-L1 expression in parental cells, and dual immunofluorescent staining of E-cadherin and PD-L1 suggests co-localization of both molecules. We also observed marked downregulation of PD-L1 in cells with E-cadherin downregulation after chronic treatment with vinorelbine. These results indicate a correlation between therapy-induced E-cadherin downregulation and decreased PD-L1 expression, highlighting the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the evaluation of resistance mechanisms but also for the determination of PD-L1 expression status.
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