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RAS-Mitogen-Activated Protein Kinase Signal Is Required for Enhanced PD-L1 Expression in Human Lung Cancers

Hidetoshi Sumimoto1, Atsushi Takano1,2, Koji Teramoto1

  • 1Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu, Shiga, Japan.

Plos One
|November 16, 2016
PubMed

Insights

MAPK signaling is a key driver of programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancer, influencing immune evasion. Targeting MAPK and STAT3 pathways shows promise for lung cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Ectopic programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancers (NSCLCs) contributes to immune evasion and is a target for immune checkpoint therapies.
  • The precise molecular mechanisms driving ectopic PD-L1 expression in NSCLCs are not fully understood.

Purpose of the Study:

  • To investigate the downstream signaling pathways responsible for ectopic PD-L1 expression in NSCLCs, with a focus on KRAS-mutant adenocarcinoma.
  • To explore the relationship between specific mutations (EGFR/KRAS) and PD-L1 expression levels.

Main Methods:

  • Utilized MEK inhibitor (U0126), ERK2 and KRAS siRNAs, and phorbol ester stimulation to assess PD-L1 regulation.
  • Employed luciferase assays to evaluate transcriptional activity at the PD-L1 gene's AP-1 site.
  • Conducted chromatin immunoprecipitation assays to confirm cJUN binding.
  • Used STAT3 siRNAs and a PI3K inhibitor (LY294002) to examine STAT3 and PI3K pathway involvement.
  • Performed supervised cluster and gene set enrichment analyses to correlate PD-L1 expression with gene pathways.

Main Results:

  • MEK inhibition significantly reduced surface PD-L1 levels by 50-60%.
  • ERK2 and KRAS knockdown decreased PD-L1 expression, while phorbol ester stimulation increased it.
  • Luciferase and ChIP assays confirmed AP-1 site transcriptional activity mediated by cJUN.
  • STAT3 siRNAs partially reduced PD-L1 in some cell lines, whereas PI3K inhibition had no effect.
  • PD-L1 expression correlated with genes involved in cell motility and adhesion.

Conclusions:

  • MAPK signaling is the dominant pathway regulating ectopic PD-L1 expression in NSCLC, with STAT3 playing a supporting role.
  • MAPK signaling influences PD-L1 expression and genes associated with enhanced cell motility.
  • Targeting MAPK and STAT3 pathways may offer novel therapeutic strategies for NSCLC.

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