MAPK pathway activity plays a key role in PD-L1 expression of lung adenocarcinoma cells

J Pathol. 2019 Sep;249(1):52-64. doi: 10.1002/path.5280. Epub 2019 May 21.


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.

Keywords: IFNγ; MAPK pathway; MHC-I; non-small cell lung cancer (NSCLC); programmed death-ligand 1 (PD-L1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / enzymology*
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / pathology
  • Antineoplastic Agents / pharmacology
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • Coculture Techniques
  • Epidermal Growth Factor / pharmacology
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Interferon-gamma / pharmacology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction


  • Antineoplastic Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Epidermal Growth Factor
  • Hepatocyte Growth Factor
  • Interferon-gamma
  • Mitogen-Activated Protein Kinases