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Regulation of programmed death ligand 1 (PD-L1) expression by TNF-related apoptosis-inducing ligand (TRAIL) in

Julio M Pimentel1,2,3, Jun-Ying Zhou1,3, Gen Sheng Wu1,2,3,4

  • 1Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

Molecular Carcinogenesis
|October 14, 2022
PubMed

Insights

Triple-negative breast cancer (TNBC) exhibits resistance to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) therapy. This study reveals that Programmed Death-Ligand 1 (PD-L1) promotes TRAIL resistance via extracellular signal-regulated kinase (ERK) activation, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted treatments.
  • Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows promise for TNBC but faces resistance.
  • Mechanisms of TRAIL resistance in TNBC are not fully understood.

Purpose of the Study:

  • To investigate the role of Programmed Death-Ligand 1 (PD-L1) in TRAIL resistance in TNBC.
  • To elucidate the underlying molecular mechanisms linking PD-L1 to TRAIL resistance.
  • To explore potential therapeutic strategies targeting PD-L1 for overcoming TRAIL resistance.

Main Methods:

  • Analysis of PD-L1 expression in TRAIL-sensitive and resistant TNBC cells.
  • Investigating the role of extracellular signal-regulated kinase (ERK) pathway in regulating PD-L1.
  • Utilizing siRNA and pharmacological inhibitors (U0126) to modulate ERK and PD-L1.
  • Assessing the impact of PD-L1 manipulation on TRAIL-induced apoptosis.

Main Results:

  • TRAIL treatment increased PD-L1 expression in sensitive cells; resistant cells showed higher basal PD-L1.
  • Increased PD-L1 expression correlated with elevated ERK activation.
  • ERK inhibition (U0126) or knockdown reduced PD-L1 and enhanced TRAIL-induced cell death.
  • PD-L1 knockout/knockdown potentiated TRAIL-induced apoptosis, independent of immune evasion.

Conclusions:

  • PD-L1 plays a significant role in mediating TRAIL resistance in TNBC through a noncanonical mechanism.
  • The ERK pathway regulates PD-L1 expression, contributing to TRAIL resistance.
  • Targeting PD-L1, potentially in combination with TRAIL, could overcome therapeutic resistance in TNBC.
Keywords:
ERKPD-L1TNBCTRAILresistance

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