VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

Rozanne Arulanandam; Cory Batenchuk; Fernando A Angarita; Kathryn Ottolino-Perry; Sophie Cousineau; Amelia Mottashed; Emma Burgess; Theresa J Falls; Naomi De Silva; Jovian Tsang; Grant A Howe; Marie-Claude Bourgeois-Daigneault; David P Conrad; Manijeh Daneshmand; Caroline J Breitbach; David H Kirn; Leda Raptis; Subash Sad; Harold Atkins; Michael S Huh; Jean-Simon Diallo; Brian D Lichty; Carolina S Ilkow; Fabrice Le Boeuf; Christina L Addison; J Andrea McCart; John C Bell

doi:10.1016/j.ccell.2015.06.009

VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

Cancer Cell. 2015 Aug 10;28(2):210-24. doi: 10.1016/j.ccell.2015.06.009. Epub 2015 Jul 23.

Authors

Rozanne Arulanandam¹, Cory Batenchuk¹, Fernando A Angarita², Kathryn Ottolino-Perry², Sophie Cousineau¹, Amelia Mottashed¹, Emma Burgess¹, Theresa J Falls¹, Naomi De Silva¹, Jovian Tsang¹, Grant A Howe¹, Marie-Claude Bourgeois-Daigneault¹, David P Conrad¹, Manijeh Daneshmand¹, Caroline J Breitbach³, David H Kirn³, Leda Raptis⁴, Subash Sad⁵, Harold Atkins¹, Michael S Huh¹, Jean-Simon Diallo¹, Brian D Lichty⁶, Carolina S Ilkow¹, Fabrice Le Boeuf¹, Christina L Addison¹, J Andrea McCart⁷, John C Bell⁸

Affiliations

¹ Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
² Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 2M9, Canada.
³ SillaJen Biotherapeutics, San Francisco, CA 94111-3380, USA.
⁴ Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
⁵ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
⁶ McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada.
⁷ Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 2M9, Canada; Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
⁸ Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Electronic address: jbell@ohri.ca.

PMID: 26212250
DOI: 10.1016/j.ccell.2015.06.009

Abstract

Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1. PRD1-BF1 does not contribute to the mitogenic effects of VEGF, but directly represses genes involved in type I interferon (IFN)-mediated antiviral signaling. In vivo suppression of VEGF signaling diminishes PRD1-BF1/Blimp1 expression in tumor vasculature and inhibits intravenously administered oncolytic vaccinia delivery to and consequent spread within the tumor.

MeSH terms

Animals
Cell Line
Cell Line, Tumor
Cells, Cultured
Gene Expression / drug effects
Gene Expression Profiling
Host-Pathogen Interactions
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Human Umbilical Vein Endothelial Cells / virology
Humans
Mice, Inbred C57BL
Microscopy, Fluorescence
Neoplasms / blood supply
Neoplasms / therapy
Neoplasms / virology*
Neovascularization, Pathologic / genetics
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / virology
Oncolytic Viruses / physiology*
Positive Regulatory Domain I-Binding Factor 1
RNA Interference
Receptors, Vascular Endothelial Growth Factor / genetics
Receptors, Vascular Endothelial Growth Factor / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcriptional Activation / drug effects
Vaccinia virus / physiology
Vascular Endothelial Growth Factor A / pharmacology*

Substances

Prdm1 protein, mouse
Repressor Proteins
Transcription Factors
Vascular Endothelial Growth Factor A
PRDM1 protein, human
Positive Regulatory Domain I-Binding Factor 1
Receptors, Vascular Endothelial Growth Factor