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JAK/STAT inhibition with ruxolitinib enhances oncolytic virotherapy in non-small cell lung cancer models

Cancer Gene Therapy volume 26, pages 411–418 (2019)Cite this article

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Abstract

The concept of using viruses to treat cancer has now shown proof of concept in several recent clinical trials, leading to the first FDA approval of virotherapy for melanoma last year. Vesicular stomatitis virus (VSV) is a promising oncolytic virus that has inhibitory effects on a number of cancer types including non-small cell lung cancer. One of the major mechanisms of resistance to VSV infection is the type I interferon (IFN) response, leading to the development of VSV expressing IFNβ which will lead to resistance of viral replication in normal cells which have intact IFN signaling but allow replication in cancer cells with defective IFNβ signaling. However, some cancer cells have intact or partially intact IFN signaling pathways leading to resistance to virotherapy. Here we utilized JAK/STAT inhibitor, ruxolitinib, in combination with VSV-IFNβ to see if inhibition of JAK/STAT signaling will enhance VSV-IFNβ therapy for lung cancer. We used five human and two murine NSCLC cell lines in vitro, and the combination treatment was assayed for cytotoxicity. We performed western blots on treated cells to see the effects of ruxolitinib on JAK/STAT signaling and PDL-1 expression in treated cells. Finally, the combination of VSV-IFNβ and ruxolitinib was tested in an immune competent murine model of NSCLC. Ruxolitinib enhanced virotherapy in resistant and sensitive NSCLC cells. The addition of ruxolitinib inhibited STAT1 phosphorylation and to a lesser extent STAT3 phosphorylation. Ruxolitinib treatment prevented NSCLC cells from enhancing PDL-1 expression in response to virotherapy. Combination ruxolitinib and VSV-IFNβ therapy resulted in a trend toward improved survival of mice without substantially effecting PDL-1 levels or levels of immune infiltration into the tumor. These results support further clinical evaluation of the combination of JAK/STAT inhibition with virotherapy.

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Acknowledgements

This work was funded, in part, by A Breath Of Hope Lung Foundation Fellowship Award and by Departmental funds at the University of Minnesota.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA

    Manish R. Patel, Blake A. Jacobson & Robert A. Kratzke

  2. Department of Biology, Macalester College, St. Paul, MN, USA

    Alexander Dash, Daniel Baumann & Kareem Ismail

  3. Health Partners, Regions Hospital, St. Paul, MN, USA

    Yan Ji

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  1. Manish R. Patel
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Correspondence to Manish R. Patel.

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MRP is currently site principal investigator of a phase I study of VSV-IFNβ-NIS sponsored by the manufacturer, Vyriad, without any financial compensation. The authors declare that they have no conflict of interest.

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Patel, M.R., Dash, A., Jacobson, B.A. et al. JAK/STAT inhibition with ruxolitinib enhances oncolytic virotherapy in non-small cell lung cancer models. Cancer Gene Ther 26, 411–418 (2019). https://doi.org/10.1038/s41417-018-0074-6

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