Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma

Neuro Oncol. 2017 Oct 1;19(10):1338-1349. doi: 10.1093/neuonc/nox051.

Abstract

Background: Interferons (IFNs) are cytokines typically induced upon viral infection but are constitutively expressed also in the absence of acute infection. The physiological role of autocrine and paracrine IFN signaling, however, remains poorly understood, and its function in glioblastoma has not been explored in depth.

Methods: Using RNA interference-mediated gene silencing, we characterized constitutive type I IFN signaling and its role in human glioma cells.

Results: We observed constitutive expression of phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and myxovirus resistance protein A (MxA), a classical IFN-response marker, in the absence of exogenous IFN-β. In vivo, we found higher MxA expression in gliomas than in normal tissue, suggesting that IFN signaling is constitutively active in these tumors. To demonstrate the presence of an autocrine type I IFN signaling loop in glioma cells in vitro, we first confirmed the expression of the type I alpha/beta receptor (IFNAR)1/2, and its ligands, IFN-α and IFN-β. Small interfering RNA-mediated receptor gene silencing resulted in reduced expression of MxA at mRNA and protein levels, as did gene silencing of the ligands, corroborating the hypothesis of an autocrine signaling loop in which type I IFNs induce intracellular signaling through IFNAR1/2. On a functional level, following IFNAR1 or IFNAR2 gene silencing, we observed reduced programmed death ligand 1 (PD-L1) and major histocompatibility complex (MHC) class I and II expression as well as an enhanced susceptibility to natural killer immune cell lysis, suggesting that autocrine IFN signaling contributes to the immune evasion of glioma cells.

Conclusions: Our findings point to an important role of constitutive IFN signaling in glioma cells by modulating their interaction with the microenvironment.

Keywords: PD-L1; STAT1; glioma; immunogenicity; interferon.

MeSH terms

  • Autocrine Communication / immunology*
  • Cell Line, Tumor
  • Cytokines / immunology
  • Glioblastoma / immunology*
  • Humans
  • Interferon-alpha / immunology*
  • Phosphorylation
  • Receptor, Interferon alpha-beta / immunology
  • Signal Transduction / immunology*
  • Tumor Escape

Substances

  • Cytokines
  • IFNAR1 protein, human
  • IFNAR2 protein, human
  • Interferon-alpha
  • Receptor, Interferon alpha-beta