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Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model

Gene Therapy volume 22, pages 65–75 (2015)Cite this article

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Abstract

In our earlier studies, Semliki Forest virus vector VA7 completely eliminated type I interferon (IFN-I)-unresponsive human U87-luc glioma xenografts, whereas interferon-responsive mouse gliomas proved refractory. Here, we describe in two clones of CT26 murine colon carcinoma, opposed patterns of IFN-I responsiveness and sensitivity to VA7. Both CT26WT and CT26LacZ clones secreted biologically active interferon in vitro upon virus infection but only CT26WT cells were protected. Focal infection of CT26WT cultures was self-limiting but could be rescued using IFN-I pathway inhibitor Ruxolitinib or antibody against IFNβ. Whole transcriptome sequencing (RNA-Seq) and protein expression analysis revealed that CT26WT cells constitutively expressed 56 different genes associated with pattern recognition and IFN-I signaling pathways, spanning two reported anti-RNA virus gene signatures and 22 genes with reported anti-alphaviral activity. Whereas CT26WT tumors were strictly virus-resistant in vivo, infection of CT26LacZ tumors resulted in complete tumor eradication in both immunocompetent and severe combined immune deficient mice. In double-flank transplantation experiments, CT26WT tumors grew despite successful eradication of CT26LacZ tumors from the contralateral flank. Tumor growth progressed uninhibited also when CT26LacZ inoculums contained only a small fraction of CT26WT cells, demonstrating dominance of IFN responsiveness when heterogeneous tumors are targeted with interferon-sensitive oncolytic viruses.

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Acknowledgements

We want to thank Diana Schenkwein from A.I. Virtanen Institute for Molecular Sciences for her expert advice and the staff of the lab animal centers for their professional support. MV-K was funded by the Academy of Finland (grant number 125186), Canadian Institutes of Health Research and Terry Fox Foundation, Canada. JB was supported by an Industrial Fellowship from the Canadian Institutes of Health Research and Terry Fox Foundation (TFF 122868). AH was financially supported by the Academy of Finland (grant number 137958), Emil Aaltonen Foundation, Medicinska Understödsföreningen Liv och Hälsa, the Finnish Cancer Foundations, the strategic funding for the Cancer Center of the University of Eastern Finland, DPMM graduate school, State Funding for University Hospitals (EVO) and Orion Foundation.

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Authors and Affiliations

  1. Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    J J Ruotsalainen, M U Kaikkonen, M Niittykoski, M W Martikainen, S Ylä-Herttuala & A E Hinkkanen

  2. Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada

    C G Lemay, J Cox, N S De Silva, A Kus, T J Falls, J-S Diallo, F Le Boeuf, J C Bell & M J Vähä-Koskela

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  1. J J Ruotsalainen
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Correspondence to A E Hinkkanen.

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John Bell is co-founder of Jennerex Biotherapeutics and sits on the Board of Directors. The remaining authors declare no conflict of interest.

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Ruotsalainen, J., Kaikkonen, M., Niittykoski, M. et al. Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model. Gene Ther 22, 65–75 (2015). https://doi.org/10.1038/gt.2014.83

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