RRC ID 65469
Author Okita R, Maeda A, Shimizu K, Nojima Y, Saisho S, Nakata M.
Title PD-L1 overexpression is partially regulated by EGFR/HER2 signaling and associated with poor prognosis in patients with non-small-cell lung cancer.
Journal Cancer Immunol Immunother
Abstract Immunocheckpoint inhibitors targeting the programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) axis have shown promising results in patients with non-small-cell lung cancer (NSCLC). Recent research has shown that epidermal growth factor receptor (EGFR) signaling affects PD-L1 expression in NSCLC cells; however, the mechanism regulating PD-L1 expression in tumor cells remains unclear. Using immunohistochemistry, we evaluated the impact of expression of PD-L1 and EGF family receptors EGFR and human epidermal growth factor receptor 2 (HER2) in tumor cells from 91 patients with pathological Stage IA-IIIA NSCLC. Overexpression of PD-L1 was observed in 14% of the resected tumors, and associated with poor recurrence-free survival (p = 0.021) and overall survival (p = 0.033). PD-L1 expression is positively correlated with EGFR expression and inversely correlated with HER2. NSCLC cell lines were treated in vitro with the EGFR ligand EGF with or without inhibition of EGFR or HER2, after which PD-L1 expression was evaluated using flow cytometry. Consistent with previous reports, PD-L1 expression was clearly enhanced by EGF. EGFR-tyrosine kinase inhibitors or EGFR small interfering RNA (siRNA) blocked EGF-induced PD-L1 overexpression in NSCLC cell lines, but HER2 siRNA did not. Moreover, our findings suggest that PD-L1 expression could be partially regulated via the PI3K/AKT and JAK/STAT pathways. We conclude that PD-L1 overexpression is associated with poor prognosis and is positively correlated with EGFR expression but inversely correlated with HER2 expression in NSCLC. We also showed that EGFR and HER2 have different effects on EGF-induced PD-L1 expression in NSCLC cell lines.
Volume 66(7)
Pages 865-876
Published 2017-7-1
DOI 10.1007/s00262-017-1986-y
PII 10.1007/s00262-017-1986-y
PMID 28341875
MeSH A549 Cells Adult Aged Aged, 80 and over B7-H1 Antigen / antagonists & inhibitors B7-H1 Antigen / genetics B7-H1 Antigen / metabolism* Carcinoma, Non-Small-Cell Lung / diagnosis* Carcinoma, Non-Small-Cell Lung / mortality Carcinoma, Non-Small-Cell Lung / pathology Disease-Free Survival ErbB Receptors / genetics ErbB Receptors / metabolism* Female Flow Cytometry Humans Immunohistochemistry Lung Neoplasms / diagnosis* Lung Neoplasms / mortality Lung Neoplasms / pathology Male Middle Aged Molecular Targeted Therapy Prognosis RNA, Small Interfering / genetics Receptor, ErbB-2 / genetics Receptor, ErbB-2 / metabolism* Recurrence
IF 5.442
Human and Animal Cells A549 LC-2/ad(RCB0440) RERF-LC-KJ(RCB1313)