Abstract
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 IFNγ, EGFR and MAPK signaling correlated with CD274 gene expression in lung adenocarcinoma. In a representative lung adenocarcinoma cell line panel, stimulation with EGF or IFNγ increased CD274 mRNA and PD‐L1 protein and membrane levels, which were further enhanced by combining EGF and IFNγ. 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 IFNγ‐induced CD274 mRNA and PD‐L1 protein and membrane upregulation, but had no effect on IFNγ‐induced MHC‐I upregulation. Interestingly, although IFNγ 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 IFNγ‐induced PD‐L1 expression in lung adenocarcinoma without targetable genetic alterations and may present a target to improve the efficacy of immunotherapy. © 2019 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
After years of limited progress in the treatment of advanced non-small cell lung cancer (NSCLC), a major leap forward has been made with the introduction of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) targeting immune checkpoint inhibitors
This suggests that activation of the MAPK, PI3K/mTOR and IFNγ pathways is related to increased CD274 mRNA levels in lung adenocarcinomas without targetable genetic alterations
In this study we revealed a correlation between MAPK pathway activation and CD274 expression in lung adenocarcinomas without targetable genetic alterations using The Cancer Genome Atlas (TCGA) RNA sequencing data
Summary
After years of limited progress in the treatment of advanced non-small cell lung cancer (NSCLC), a major leap forward has been made with the introduction of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) targeting immune checkpoint inhibitors. These have greatly improved the overall survival of patients with advanced NSCLC, especially patients without targetable genetic alterations, accounting for almost 60% of NSCLC [1,2,3]. PD-L1 on tumor cells binds to PD-1 on T cells, disrupting T cell function and thereby preventing an effective tumor immune response [9] Oncogenic driver mutations, such as mutations in EGFR, ALK and BRAF, are known inducers of PD-L1 expression in NSCLC cells. In these oncogene-activated cells, the PI3K/mTOR, JAK/STAT and MAPK pathways are the main drivers of PD-L1 expression [10,11,12,13]
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