Induction of antiviral genes by the tumor microenvironment confers resistance to virotherapy

Sci Rep. 2013;3:2375. doi: 10.1038/srep02375.

Abstract

Oncolytic viruses obliterate tumor cells in tissue culture but not against the same tumors in vivo. We report that macrophages can induce a powerfully protective antiviral state in ovarian and breast tumors, rendering them resistant to oncolytic virotherapy. These tumors have activated JAK/STAT pathways and expression of interferon-stimulated genes (ISGs) is upregulated. Gene expression profiling (GEP) of human primary ovarian and breast tumors confirmed constitutive activation of ISGs. The tumors were heavily infiltrated with CD68+ macrophages. Exposure of OV-susceptible tumor cell lines to conditioned media from RAW264.7 or primary macrophages activated antiviral ISGs, JAK/STAT signaling and an antiviral state. Anti-IFN antibodies and shRNA knockdown studies show that this effect is mediated by an extremely low concentration of macrophage-derived IFNβ. JAK inhibitors reversed the macrophage-induced antiviral state. This study points to a new role for tumor-associated macrophages in the induction of a constitutive antiviral state that shields tumors from viral attack.

MeSH terms

  • Antiviral Agents / administration & dosage
  • Antiviral Agents / metabolism*
  • Cell Line, Tumor
  • Humans
  • Macrophages / metabolism
  • Macrophages / virology*
  • Neoplasm Proteins / metabolism*
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / virology*
  • Oncolytic Virotherapy / methods*
  • Tumor Microenvironment*

Substances

  • Antiviral Agents
  • Neoplasm Proteins