Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation

J Thorac Oncol. 2015 Jun;10(6):910-23. doi: 10.1097/JTO.0000000000000500.


Introduction: Epidermal growth factor receptor (EGFR) mutation status was reported to be associated with programmed death-ligand 1 (PD-L1) expression. However, the molecular mechanism of PD-L1 regulation by EGFR activation and the potential clinical significance of blocking PD-1/PD-L1 in EGFR-mutant non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs) were largely unknown.

Methods: Western blot, real-time polymerase chain reaction, immunofluorescence, and flow cytometry were employed to explore the association between PD-L1 and EGFR activation. Then, we used EGFR-TKIs and downstream pathways inhibitors to clarify the detailed signaling pathway involved in PD-L1 regulation. Cell apoptosis, viability, and enzyme-linked immunosorbent assay test were used to study the immune suppression by EGFR activation and immune reactivation by EGFR-TKIs and/or PD-1 blocking in tumor cells and human peripheral blood mononuclear cells coculture system.

Results: We found that EGFR activation by EGF stimulation, exon-19 deletions, and L858R mutation could induce PD-L1 expression. EGFR activation upregulated PD-L1 through p-ERK1/2/p-c-Jun but not through p-AKT/p-S6 pathway. PD-L1 mediated by EGFR activation could induce the apoptosis of T cells through PD-L1/PD-1 axis in tumor cells and peripheral blood mononuclear cells coculture system. Inhibiting EGFR by EGFR-TKIs could free the inhibition of T cells and enhance the production of interferon-γ. Synergistic tumor cell killing effects were not observed with EGFR-TKIs and anti-PD-1 antibody combination treatment in coculture system.

Conclusions: Our results imply that EGFR-TKIs could not only directly inhibit tumor cell viability but also indirectly enhance antitumor immunity through the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for EGFR-TKI sensitive patients, especially for EGFR-TKIs resistant NSCLC patients with EGFR mutation. Combination of EGFR-TKIs and anti-PD-1/PD-L1 antibodies treatment in NSCLC is not supported by the current study but warrant more studies to move into clinical practice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology*
  • B7-H1 Antigen / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Cell Line, Tumor
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / immunology*
  • ErbB Receptors / metabolism
  • Exons
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Molecular Targeted Therapy
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Sequence Deletion
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Tumor Escape / drug effects
  • Up-Regulation


  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Protein Kinase Inhibitors
  • Interferon-gamma
  • EGFR protein, human
  • ErbB Receptors