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 biology1. 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.
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Acknowledgements
This work was funded by grants from the Terry Fox Research Foundation (201201TFF-271514-TFF-AYDP-29782) and the Canadian Institutes of Health Research (314043) to J.C.B., J.-S.D., D.F.S., B.D.L. and R.C.A. C.S.I. is the recipient of a Fellowship award from the Alberta Innovative Health Solutions. J.C.B., D.F.S. and B.D.L. are supported by the Ontario Institute for Cancer Research and the Ottawa Regional Cancer Foundation. M.M. is funded by the Canadian Institutes of Health Research Frederick Banting and Charles Best Master's Award. C.B. is funded by the Natural Sciences and Engineering Research Council of Canada. We thank C. Cemeus and D. Vaillant for their exceptional technical support as well as members of the Bell, Auer, Atkins and Diallo laboratories for feedback on this project. pWPI-spbFGF plasmid was a gift from J. Kiss and P. Salmon (University of Geneva Medical School). HSV-1 N212 expressing GFP14,36 was a gift from K. Mossman (McMaster University). Reovirus was a gift from P. Lee (Dalhousie University). Rabbit anti-reovirus T3 antibody was a gift from E. Brown (University of Ottawa).
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C.S.I., M.M., C.B., D.B.N., S.C., F.L.B., S.H.T., J.M., M. Boileau, D.B., L.S., P.S., H.L.A. and V.A.J. conducted in vitro experiments. C.S.I., M.M., T.F., C.T.d.S. and D.B.N. performed mouse experiments. P.P. and A.C. recruited individuals with pancreatic cancer and collected biopsies from subjects with pancreatic cancer. R.M.S., M. Burdick and A.C. isolated normal and cancer-associated fibroblasts. A.A., J.Z. and R.C.A. engineered the MG1-FGF2 virus. C.S.I., M.M., C.B., A.A., C.L.A., D.F.S., J.-S.D., B.D.L. and J.C.B. designed the study and were involved in writing of the manuscript.
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Ilkow, C., Marguerie, M., Batenchuk, C. et al. Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity. Nat Med 21, 530–536 (2015). https://doi.org/10.1038/nm.3848
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DOI: https://doi.org/10.1038/nm.3848
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