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

Cell Rep. 2017 May 9;19(6):1189-1201. doi: 10.1016/j.celrep.2017.04.031.

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.

Keywords: IRF1; JAK-STATs; PD-1; PD-L1; PD-L2; immunotherapy; interferon receptor signaling pathways; melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / genetics*
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism*
  • Interferon-beta / metabolism
  • Interferon-gamma / metabolism
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / metabolism
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Programmed Cell Death 1 Ligand 2 Protein / genetics*
  • Programmed Cell Death 1 Ligand 2 Protein / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • STAT Transcription Factors / metabolism
  • Signal Transduction*
  • Transcriptional Activation*
  • Up-Regulation

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • STAT Transcription Factors
  • Interferon-beta
  • Interferon-gamma
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2