PD-L1 overexpression is partially regulated by EGFR/HER2 signaling and associated with poor prognosis in patients with non-small-cell lung cancer.
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.
Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
Riki
http://orcid.org/0000-0003-1343-1275
R
Okita
Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
Ai
A
Maeda
Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
Katsuhiko
K
Shimizu
Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
Yuji
Y
Nojima
Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
Shinsuke
S
Saisho
Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
Masao
M
Nakata
D000072283:A549 Cells; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence
D060890:B7-H1 Antigen; D066246:ErbB Receptors; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C423236:CD274 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human
EGFR; HER2; Non-small-cell lung cancer (NSCLC); PD-L1; Prognostic factor