PD-L1 protein expression in non-small-cell lung cancer and its relationship with the hypoxia-related signaling pathways: A study based on immunohistochemistry and RNA sequencing data

Abstract

OBJECTIVES: Therapies that target programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Hypoxia-related genes are also important regulators of PD-L1, and the role of PD-L1 in NSCLC is still not clear. The objective of this study was to investigate PD-L1 expression and its correlation with hypoxic-inducible factor 1alpha (HIF1A), vascular endothelial growth factor A (VEGFA), glucose transporter 1 (GLUT1), and carbonic anhydrase 9 (CAIX) expression in NSCLC patients. The association between PD-L1 expression and survival was also determined. MATERIALS AND METHODS: PD-L1/protein expression was evaluated in 295 resected NSCLCs and its correlation with HIF1A, VEGFA, GLUT1, CAIX expression and survival was determined based on immunohistochemical and RNA sequencing data obtained from The Cancer Genome Atlas (TCGA) database. RESULTS: PD-L1 protein expression was significantly correlated with HIF1A, VEGFA, GLUT1, and CAIX expression only in adenocarcinoma when a 10% or a 50% cut-off was used. PD-L1 mRNA expression was also significantly correlated with HIF1A, VEGFA, GLUT1, and CAIX expression in adenocarcinoma. Univariate analysis revealed that HIF1A expression was associated with poor recurrence-free survival (RFS), and GLUT1 was associated with poor overall survival (OS) and RFS. GLUT1 was an independent prognostic factor for OS in multivariate analysis of immunohistochemical and TCGA data (p = 0.024 and 0.029, respectively). Patients with low expression of both PD-L1 and GLUT1 had longer OS than other patterns in immunohistochemical and TCGA data (p = 0.003 and 0.051, respectively). CONCLUSIONS: PD-L1 protein and mRNA expression were correlated with HIF1A, VEGFA, GLUT1, and CAIX expression in adenocarcinoma alone. Low expression of GLUT1 and low expression of both PD-L1 and GLUT1 were associated with improved prognosis. Our findings support the rationale for co-targeting hypoxia-related genes and PD-L1 in cancer therapy. Expression of hypoxia-related genes may be helpful in selecting patients appropriate for PD-L1 therapy.