title: Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow.
abstract: Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses.
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Breitbach
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Paterson
authors.forename: Chantal G
authors.initials: CG
authors.lastname: Lemay
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Falls
authors.forename: Allison
authors.initials: A
authors.lastname: McGuire
authors.forename: Kelley A
authors.initials: KA
authors.lastname: Parato
authors.forename: David F
authors.initials: DF
authors.lastname: Stojdl
authors.forename: Manijeh
authors.initials: M
authors.lastname: Daneshmand
authors.forename: Kelly
authors.initials: K
authors.lastname: Speth
authors.forename: David
authors.initials: D
authors.lastname: Kirn
authors.forename: J Andrea
authors.initials: JA
authors.lastname: McCart
authors.forename: Harold
authors.initials: H
authors.lastname: Atkins
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001783:Blood Flow Velocity; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays