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Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression.

  • Author(s): Garcia-Diaz, Angel
  • Shin, Daniel Sanghoon
  • Moreno, Blanca Homet
  • Saco, Justin
  • Escuin-Ordinas, Helena
  • Rodriguez, Gabriel Abril
  • Zaretsky, Jesse M
  • Sun, Lu
  • Hugo, Willy
  • Wang, Xiaoyan
  • Parisi, Giulia
  • Saus, Cristina Puig
  • Torrejon, Davis Y
  • Graeber, Thomas G
  • Comin-Anduix, Begonya
  • Hu-Lieskovan, Siwen
  • Damoiseaux, Robert
  • Lo, Roger S
  • Ribas, Antoni
  • et al.
Abstract

PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter. PD-L2 responded equally to interferon beta and gamma and is regulated through both IRF1 and STAT3, which bind to the PD-L2 promoter. Analysis of biopsy specimens from patients with melanoma confirmed interferon signature enrichment and upregulation of gene targets for STAT1/STAT2/STAT3 and IRF1 in anti-PD-1-responding tumors. Therefore, these studies map the signaling pathway of interferon-gamma-inducible PD-1 ligand expression.

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