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


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.

DOI: 10.1038/nm.3848

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@article{Ilkow2015ReciprocalCC, title={Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.}, author={Carolina S. Ilkow and Monique Marguerie and Cory Batenchuk and Justin Mayer and Daniela Ben Neriah and Sophie Cousineau and Theresa J. Falls and Victoria Ann Jennings and Meaghan Boileau and David P. Bellamy and Donald Bastin and Christiano Tanese de Souza and Almohanad A. Alkayyal and Jiqing Zhang and Fabrice Le Boeuf and Rozanne Arulanandam and Lawton J Stubbert and Padma D Sampath and Steve Thorne and Piriya Paramanthan and Avijit Chatterjee and Robert M. Strieter and Marie D. Burdick and Christina L Addison and David F. Stojdl and Harold L Atkins and Rebecca Ann C Auer and Jean-Simon Diallo and Brian D. Lichty and John Cameron Bell}, journal={Nature medicine}, year={2015}, volume={21 5}, pages={530-6} }