Original Articles
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

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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.

Key Words

PD-L1
PD-1
EGFR
Tyrosine kinase inhibitors
NSCLC

Cited by (0)

Nan Chen, Wenfeng Fang, and Jianhua Zhan contributed equally to this work.

This work was supported by grants from the Chinese National Natural Science Foundation project (Grant Nos. 81372502 and 81201917), the National High Technology Research and Development Program of China (863 Program Nos. 2012AA02A501 and 2012AA02A502), the Natural Science Foundation of Guangdong (Grant No. S2013010016564), the Major Project of Health Collaborative Innovation of Guangzhou City (201400000001-2), the Specialized Research Fund for the Doctoral Program of Higher Education (20120171120116), the Young Teacher Training Program of Sun Yat-Sen University (14ykpy38), the Physician-Scientist Cultivation Project of Sun Yat-Sen University Cancer Center (04140701), and Wu Jieping Medical Foundation Project (Grant No: 320.6750.131, 3206740.10012). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosures: The authors declare no conflicts of interest.