Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have improved the survival of patients with non-small cell lung cancer (NSCLC). Still, many patients do not respond to these inhibitors. PD-L1 (CD274) expression, one of the factors that influences the efficacy of immune checkpoint inhibitors, is dynamic. Here, we studied the regulation of PD-L1 expression in NSCLC without targetable genetic alterations in EGFR, ALK, BRAF, ROS1, MET, ERBB2 and RET. Analysis of RNA sequencing data from these NSCLCs revealed that inferred IFN gamma, EGFR and MAPK signaling correlated with CD274 gene expression in lung adenocarcinoma. In a representative lung adenocarcinoma cell line panel, stimulation with EGF or IFN gamma increased CD274 mRNA and PD-L1 protein and membrane levels, which were further enhanced by combining EGF and IFN gamma. Similarly, tumor cell PD-L1 membrane levels increased after coculture with activated peripheral blood mononuclear cells. Inhibition of the MAPK pathway, using EGFR inhibitors cetuximab and erlotinib or the MEK 1 and 2 inhibitor selumetinib, prevented EGF- and IFN gamma-induced CD274 mRNA and PD-L1 protein and membrane upregulation, but had no effect on IFN gamma-induced MHC-I upregulation. Interestingly, although IFN gamma increases transcriptional activity of CD274, MAPK signaling also increased stabilization of CD274 mRNA. In conclusion, MAPK pathway activity plays a key role in EGF- and IFN gamma-induced PD-L1 expression in lung adenocarcinoma without targetable genetic alterations and may present a target to improve the efficacy of immunotherapy. (c) 2019 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
- non-small cell lung cancer (NSCLC)
- programmed death-ligand 1 (PD-L1)
- IFN gamma
- MAPK pathway
- ACTIVATED PROTEIN-KINASE
- BREAST-CANCER CELLS