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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hanahan, D. & Coussens, L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Chung, A.S. et al. An interleukin-17–mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat. Med. 19, 1114–1123 (2013).
Hwang, R.F. et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918–926 (2008).
Lisanti, M.P., Martinez-Outschoorn, U.E. & Sotgia, F. Oncogenes induce the cancer-associated fibroblast phenotype: Metabolic symbiosis and “fibroblast addiction” are new therapeutic targets for drug discovery. Cell Cycle 12, 2723–2732 (2013).
Nakasone, E.S. et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).
Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).
Sun, Y. et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 18, 1359–1368 (2012).
Wilson, T.R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).
Breitbach, C.J. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011).
Heo, J. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. Med. 19, 329–336 (2013).
Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).
Löhr, M. et al. Transforming growth factor-β1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 61, 550–555 (2001).
Rønnov-Jessen, L. & Petersen, O.W. Induction of αα-smooth muscle actin by transforming growth factor-β1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68, 696–707 (1993).
Sobol, P.T. et al. Adaptive antiviral immunity is a determinant of the therapeutic success of oncolytic virotherapy. Mol. Ther. 19, 335–344 (2011).
Stojdl, D.F. et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 4, 263–275 (2003).
Brun, J. et al. Identification of genetically modified Maraba virus as an oncolytic rhabdovirus. Mol. Ther. 18, 1440–1449 (2010).
Azzarone, B. et al. Abnormal properties of skin fibroblasts from patients with breast cancer. Int. J. Cancer. 33, 759–764 (1984).
Brouty-Boyé, D. et al. Fetal myofibroblast-like cells isolated from post-radiation fibrosis in human breast cancer. Int. J. Cancer. 47, 697–702 (1991).
Schor, S.L., Schor, A.M. & Rushton, G. Fibroblasts from cancer patients display a mixture of both foetal and adult-like phenotypic characteristics. J. Cell Sci. 90, 401–407 (1988).
Cirri, P. & Chiarugi, P. Cancer associated fibroblasts: the dark side of the coin. Am. J. Cancer Res. 1, 482–497 (2011).
Erez, N., Truitt, M., Olson, P., Arron, S.T. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB–dependent manner. Cancer Cell 17, 135–147 (2010).
Franco, O.E., Shaw, A.K., Strand, D.W. & Hayward, S.W. Cancer associated fibroblasts in cancer pathogenesis. Semin. Cell Dev. Biol. 21, 33–39 (2010).
Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).
Räsänen, K. & Vaheri, A. Activation of fibroblasts in cancer stroma. Exp. Cell Res. 316, 2713–2722 (2010).
Spaeth, E.L. et al. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS ONE 4, e4992 (2009).
Ablasser, A. et al. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III––transcribed RNA intermediate. Nat. Immunol. 10, 1065–1072 (2009).
Chiu, Y.H., Macmillan, J.B. & Chen, Z.J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576–591 (2009).
Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).
Altomonte, J. & Ebert, O. Sorting out Pandora's box: discerning the dynamic roles of liver microenvironment in oncolytic virus therapy for hepatocellular carcinoma. Front. Oncol. 4, 85 (2014).
Kurozumi, K. et al. Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy. J. Natl. Cancer Inst. 99, 1768–1781 (2007).
Stanford, M.M., Breitbach, C.J., Bell, J.C. & McFadden, G. Innate immunity, tumor microenvironment and oncolytic virus therapy: friends or foes? Curr. Opin. Mol. Ther. 10, 32–37 (2008).
Kim, R., Emi, M. & Tanabe, K. Cancer immunoediting from immune surveillance to immune escape. Immunology 121, 1–14 (2007).
Lichty, B.D., Breitbach, C.J., Stojdl, D.F. & Bell, J.C. Going viral with cancer immunotherapy. Nat. Rev. Cancer 14, 559–567 (2014).
Erkan, M. et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol. Hepatol. 9, 454–467 (2012).
Erkan, M. et al. The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance. Curr. Mol. Med. 12, 288–303 (2012).
Sanfilippo, C.M. & Blaho, J.A. ICP0 gene expression is a herpes simplex virus type 1 apoptotic trigger. J. Virol. 80, 6810–6821 (2006).
Dayer, A.G. et al. Expression of FGF-2 in neural progenitor cells enhances their potential for cellular brain repair in the rodent cortex. Brain 130, 2962–2976 (2007).
Kim, J.H. et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol. Ther. 14, 361–370 (2006).
Breitbach, C.J. et al. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19, 886–894 (2011).
Emig, D. et al. AltAnalyze and DomainGraph: analyzing and visualizing exon expression data. Nucleic Acids Res. 38, W755–W762 (2010).
Eden, E., Navon, R., Steinfeld, I., Lipson, D. & Yakhini, Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10, 48 (2009).
Samarajiwa, S.A., Forster, S., Auchettl, K. & Hertzog, P.J. INTERFEROME: the database of interferon regulated genes. Nucleic Acids Res. 37, D852–D857 (2009).
Pfaffl, M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).
Östman, A. & Augsten, M. Cancer-associated fibroblasts and tumor growth–bystanders turning into key players. Curr. Opin. Genet. Dev. 19, 67–73 (2009).
Tomayko, M.M. & Reynolds, C.P. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother. Pharmacol. 24, 148–154 (1989).
Dell, R.B., Holleran, S. & Ramakrishnan, R. Sample size determination. ILAR J 43, 207–213 (2002).
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).
The authors declare no competing financial interests.
About this article
Cite this article
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
High-throughput screening in multicellular spheroids for target discovery in the tumor microenvironment
Expert Opinion on Drug Discovery (2020)
STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy
Nature Cell Biology (2020)
Intratumoral expression of IL-7 and IL-12 using an oncolytic virus increases systemic sensitivity to immune checkpoint blockade
Science Translational Medicine (2020)
Bulletin of Mathematical Biology (2020)
Cancer Gene Therapy (2020)