title: Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.
abstract: Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Carolina S
authors.initials: CS
authors.lastname: Ilkow
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Monique
authors.initials: M
authors.lastname: Marguerie
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Cory
authors.initials: C
authors.lastname: Batenchuk
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Justin
authors.initials: J
authors.lastname: Mayer
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ben Neriah
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Cousineau
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Jennings
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Boileau
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Bellamy
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Donald
authors.initials: D
authors.lastname: Bastin
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Christiano Tanese
authors.initials: CT
authors.lastname: de Souza
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.
authors.forename: Almohanad
authors.initials: A
authors.lastname: Alkayyal
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Neurosurgery, the Second Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Boeuf
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Rozanne
authors.initials: R
authors.lastname: Arulanandam
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Lawton
authors.initials: L
authors.lastname: Stubbert
authors.affiliation: 1] University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [2] Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [3] Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Padma
authors.initials: P
authors.lastname: Sampath
authors.affiliation: 1] University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [2] Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [3] Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Steve H
authors.initials: SH
authors.lastname: Thorne
authors.affiliation: The Ottawa Hospital, Division of Gastroenterology, Ottawa, Ontario, Canada.
authors.forename: Piriya
authors.initials: P
authors.lastname: Paramanthan
authors.affiliation: The Ottawa Hospital, Division of Gastroenterology, Ottawa, Ontario, Canada.
authors.forename: Avijit
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Global Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.affiliation: Department of Medicine, Pulmonary and Critical Care, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Burdick
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Addison
authors.affiliation: 1] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada. [2] Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: David F
authors.initials: DF
authors.lastname: Stojdl
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Atkins
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Auer
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
authors.affiliation: 1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
mesh_terms: D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins