Journal
NATURE MEDICINE
Volume 21, Issue 5, Pages 530-U168Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3848
Keywords
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Funding
- Terry Fox Research Foundation [201201TFF-271514-TFF-AYDP-29782]
- Canadian Institutes of Health Research [314043]
- Alberta Innovative Health Solutions
- Ontario Institute for Cancer Research
- Ottawa Regional Cancer Foundation
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
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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(1). 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-beta (TGF-beta) 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.
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