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: Carolina S Ilkow, Monique Marguerie, Cory Batenchuk, Justin Mayer, Daniela Ben Neriah, Sophie Cousineau, Theresa Falls, Victoria A Jennings, Meaghan Boileau, David Bellamy, Donald Bastin, Christiano Tanese de Souza, Almohanad Alkayyal, Jiqing Zhang, Fabrice Le Boeuf, Rozanne Arulanandam, Lawton Stubbert, Padma Sampath, Steve H Thorne, Piriya Paramanthan, Avijit Chatterjee, Robert M Strieter, Marie Burdick, Christina L Addison, David F Stojdl, Harold L Atkins, Rebecca C Auer, Jean-Simon Diallo, Brian D Lichty, John C Bell
• Journal: Nature medicine (Nat Med) Vol. 21 Issue 5 Pg. 530-6 (May 2015) ISSN: 1546-170X [Electronic] United States
• PMID: 25894825 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Transforming Growth Factor beta
• Fibroblast Growth Factor 2
• Green Fluorescent Proteins

Topics

• Aged
• Animals
• Antiviral Agents (chemistry)
• Cell Line, Tumor
• Chlorocebus aethiops
• Coculture Techniques
• Female
• Fibroblast Growth Factor 2 (metabolism)
• Fibroblasts (metabolism)
• Green Fluorescent Proteins (metabolism)
• Humans
• Lung Neoplasms (metabolism)
• Male
• Mice
• Microscopy, Fluorescence
• Middle Aged
• Neoplasm Transplantation
• Oncolytic Virotherapy (methods)
• Oncolytic Viruses (metabolism)
• Ovarian Neoplasms (metabolism)
• Signal Transduction
• Stromal Cells (metabolism)
• Transforming Growth Factor beta (metabolism)
• Tumor Microenvironment
• Vero Cells