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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 improve survival in non-small cell lung cancer (NSCLC).
• However, many NSCLC patients do not respond to ICIs, partly due to dynamic PD-L1 expression.
• Understanding PD-L1 regulation is crucial for enhancing ICI efficacy, especially in NSCLC without common targetable mutations.

Purpose of the Study:

• To investigate the regulation of PD-L1 (CD274) expression in NSCLC lacking EGFR, ALK, BRAF, ROS1, MET, ERBB2, and RET alterations.
• To determine the role of signaling pathways, including MAPK, in controlling PD-L1 expression.
• To explore potential therapeutic strategies targeting PD-L1 regulation to improve immunotherapy outcomes.

Main Methods:

• Analysis of RNA sequencing data from NSCLC patients.
• In vitro studies using lung adenocarcinoma cell lines stimulated with EGF and IFNγ.
• Assessment of PD-L1 expression and MAPK pathway activity using molecular and cellular assays.
• Inhibition of the MAPK pathway using EGFR and MEK inhibitors.

Main Results:

• Inferred IFNγ, EGFR, and MAPK signaling correlated with CD274 gene expression in lung adenocarcinoma.
• EGF and IFNγ stimulation increased CD274 mRNA and PD-L1 protein levels, further enhanced by combined stimulation.
• MAPK pathway inhibition (using cetuximab, erlotinib, or selumetinib) blocked EGF- and IFNγ-induced PD-L1 upregulation.
• MAPK signaling contributed to both transcriptional activation and mRNA stabilization of CD274.

Conclusions:

• MAPK pathway activity is a key regulator of EGF- and IFNγ-induced PD-L1 expression in lung adenocarcinoma without targetable genetic alterations.
• MAPK signaling influences PD-L1 expression through both transcriptional and post-transcriptional mechanisms.
• Targeting the MAPK pathway may represent a novel strategy to enhance the efficacy of immune checkpoint inhibitors in NSCLC.