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Nat Med. 2015 May;21(5):530-6. doi: 10.1038/nm.3848. Epub 2015 Apr 20.

Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.

Author information

1
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.
2
Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
3
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.
4
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.
5
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.
6
The Ottawa Hospital, Division of Gastroenterology, Ottawa, Ontario, Canada.
7
Global Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
8
Department of Medicine, Pulmonary and Critical Care, University of Virginia, Charlottesville, Virginia, USA.
9
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.
10
McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.

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.

PMID:
25894825
DOI:
10.1038/nm.3848
[Indexed for MEDLINE]

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