Human retrotransposons and the global shutdown of homeostatic innate immunity by oncolytic parvovirus H-1PV in pancreatic cancer
Although the oncolytic parvovirus H-1PV has entered clinical trials, predicting therapeutic success remains challenging. We investigated whether the antiviral state in tumor cells determines the parvoviral oncolytic efficacy. The interferon/interferon-stimulated genes (IFN/ISG)-circuit and its major...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
28 May 2021
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| In: |
Viruses
Year: 2021, Volume: 13, Issue: 6, Pages: 1-19 |
| ISSN: | 1999-4915 |
| DOI: | 10.3390/v13061019 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.3390/v13061019 Verlag, kostenfrei, Volltext: https://www.mdpi.com/1999-4915/13/6/1019 
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| Author Notes: | Matthias Neulinger-Muñoz, Dominik Schaack, Svetlana P. Grekova, Andrea S. Bauer, Thomas Giese, Gabriel A. Salg, Elisa Espinet, Barbara Leuchs, Anette Heller, Jürg P. F. Nüesch, Miriam Schenk, Michael Volkmar, and Nathalia A. Giese |
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| 245 | 1 | 0 | |a Human retrotransposons and the global shutdown of homeostatic innate immunity by oncolytic parvovirus H-1PV in pancreatic cancer |c Matthias Neulinger-Muñoz, Dominik Schaack, Svetlana P. Grekova, Andrea S. Bauer, Thomas Giese, Gabriel A. Salg, Elisa Espinet, Barbara Leuchs, Anette Heller, Jürg P. F. Nüesch, Miriam Schenk, Michael Volkmar, and Nathalia A. Giese |
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| 520 | |a Although the oncolytic parvovirus H-1PV has entered clinical trials, predicting therapeutic success remains challenging. We investigated whether the antiviral state in tumor cells determines the parvoviral oncolytic efficacy. The interferon/interferon-stimulated genes (IFN/ISG)-circuit and its major configurator, human endogenous retroviruses (HERVs), were evaluated using qRT-PCR, ELISA, Western blot, and RNA-Seq techniques. In pancreatic cancer cell lines, H-1PV caused a late global shutdown of innate immunity, whereby the concomitant inhibition of HERVs and IFN/ISGs was co-regulatory rather than causative. The growth-inhibitory IC50 doses correlated with the power of suppression but not with absolute ISG levels. Moreover, H-1PV was not sensitive to exogenous IFN despite upregulated antiviral ISGs. Such resistance questioned the biological necessity of the oncotropic ISG-shutdown, which instead might represent a surrogate marker for personalized oncolytic efficacy. The disabled antiviral homeostasis may modify the activity of other viruses, as demonstrated by the reemergence of endogenous AluY-retrotransposons. This way of suppression may compromise the interferogenicity of drugs having gemcitabine-like mechanisms of action. This shortcoming in immunogenic cell death induction is however amendable by immune cells which release IFN in response to H-1PV. | ||
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