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

• Published in: Cancer cell Vol. 28; no. 2; pp. 210 - 224
• Main Authors: Arulanandam, Rozanne, Batenchuk, Cory, Angarita, Fernando A., Ottolino-Perry, Kathryn, Cousineau, Sophie, Mottashed, Amelia, Burgess, Emma, Falls, Theresa J., De Silva, Naomi, Tsang, Jovian, Howe, Grant A., Bourgeois-Daigneault, Marie-Claude, Conrad, David P., Daneshmand, Manijeh, Breitbach, Caroline J., Kirn, David H., Raptis, Leda, Sad, Subash, Atkins, Harold, Huh, Michael S., Diallo, Jean-Simon, Lichty, Brian D., Ilkow, Carolina S., Le Boeuf, Fabrice, Addison, Christina L., McCart, J. Andrea, Bell, John C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.08.2015
• Subjects: 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; Receptors, Vascular Endothelial Growth Factor - genetics; Receptors, Vascular Endothelial Growth Factor - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation - drug effects; Vaccinia virus; Vaccinia virus - physiology; Vascular Endothelial Growth Factor A - pharmacology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2015.06.009

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. [Display omitted] •VEGF/VEGFR2 signaling sensitizes endothelial cells to oncolytic virus infection•PRD1-BF1 mediates immune suppression in endothelial cells downstream of VEGF•PRD1-BF1 is induced in remodelling vessels by chronic or transient VEGF stimulation•Infection of tumor vasculature orchestrated by PRD1-BF1 is critical for OV delivery Arulanandam et al. show that VEGFR2 signaling in remodelling vessels induces the transcription repressor PRD1-BF1/Blimp1, which represses the expression of genes involved in type I interferon-mediated antiviral signaling, thus allowing oncolytic virus to infect tumor vasculatures to further spread within tumors.