Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: role of type I interferon signaling

Virology. 2013 Feb 5;436(1):221-34. doi: 10.1016/j.virol.2012.11.014. Epub 2012 Dec 14.


Oncolytic virus (OV) therapy takes advantage of common cancer characteristics, such as defective type I interferon (IFN) signaling, to preferentially infect and kill cancer cells with viruses. Our recent study (Murphy et al., 2012. J. Virol. 86, 3073-87) found human pancreatic ductal adenocarcinoma (PDA) cells were highly heterogeneous in their permissiveness to vesicular stomatitis virus (VSV) and suggested at least some resistant cell lines retained functional type I IFN responses. Here we examine cellular responses to infection by the oncolytic VSV recombinant VSV-ΔM51-GFP by analyzing a panel of 11 human PDA cell lines for expression of 33 genes associated with type I IFN pathways. Although all cell lines sensed infection by VSV-ΔM51-GFP and most activated IFN-α and β expression, only resistant cell lines displayed constitutive high-level expression of the IFN-stimulated antiviral genes MxA and OAS. Inhibition of JAK/STAT signaling decreased levels of MxA and OAS and increased VSV infection, replication and oncolysis, further implicating IFN responses in resistance. Unlike VSV, vaccinia and herpes simplex virus infectivity and killing of PDA cells was independent of the type I IFN signaling profile, possibly because these two viruses are better equipped to evade type I IFN responses. Our study demonstrates heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other OVs sensitive to type I IFN responses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / genetics
  • 2',5'-Oligoadenylate Synthetase / metabolism
  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism
  • Humans
  • Interferon Type I / genetics
  • Interferon Type I / metabolism*
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / metabolism
  • Myxovirus Resistance Proteins
  • Oncolytic Virotherapy*
  • Oncolytic Viruses / genetics
  • Oncolytic Viruses / physiology*
  • Pancreatic Neoplasms / therapy*
  • Pancreatic Neoplasms / virology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rhabdoviridae Infections
  • Signal Transduction*
  • Vesicular Stomatitis
  • Vesicular stomatitis Indiana virus / genetics
  • Vesicular stomatitis Indiana virus / physiology*
  • Virus Replication


  • Biomarkers, Tumor
  • Interferon Type I
  • MX1 protein, human
  • Myxovirus Resistance Proteins
  • RNA, Messenger
  • Janus Kinases
  • 2',5'-Oligoadenylate Synthetase
  • GTP-Binding Proteins