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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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Autores principales: Neulinger-Muñoz, Matthias, Schaack, Dominik, Grekova, Svetlana P., Bauer, Andrea S., Giese, Thomas, Salg, Gabriel A., Espinet, Elisa, Leuchs, Barbara, Heller, Anette, Nüesch, Jürg P. F., Schenk, Miriam, Volkmar, Michael, Giese, Nathalia A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228339/
https://www.ncbi.nlm.nih.gov/pubmed/34071585
http://dx.doi.org/10.3390/v13061019
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author Neulinger-Muñoz, Matthias
Schaack, Dominik
Grekova, Svetlana P.
Bauer, Andrea S.
Giese, Thomas
Salg, Gabriel A.
Espinet, Elisa
Leuchs, Barbara
Heller, Anette
Nüesch, Jürg P. F.
Schenk, Miriam
Volkmar, Michael
Giese, Nathalia A.
author_facet Neulinger-Muñoz, Matthias
Schaack, Dominik
Grekova, Svetlana P.
Bauer, Andrea S.
Giese, Thomas
Salg, Gabriel A.
Espinet, Elisa
Leuchs, Barbara
Heller, Anette
Nüesch, Jürg P. F.
Schenk, Miriam
Volkmar, Michael
Giese, Nathalia A.
author_sort Neulinger-Muñoz, Matthias
collection PubMed
description 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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spelling pubmed-82283392021-06-26 Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer Neulinger-Muñoz, Matthias Schaack, Dominik Grekova, Svetlana P. Bauer, Andrea S. Giese, Thomas Salg, Gabriel A. Espinet, Elisa Leuchs, Barbara Heller, Anette Nüesch, Jürg P. F. Schenk, Miriam Volkmar, Michael Giese, Nathalia A. Viruses Article 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. MDPI 2021-05-28 /pmc/articles/PMC8228339/ /pubmed/34071585 http://dx.doi.org/10.3390/v13061019 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Neulinger-Muñoz, Matthias
Schaack, Dominik
Grekova, Svetlana P.
Bauer, Andrea S.
Giese, Thomas
Salg, Gabriel A.
Espinet, Elisa
Leuchs, Barbara
Heller, Anette
Nüesch, Jürg P. F.
Schenk, Miriam
Volkmar, Michael
Giese, Nathalia A.
Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer
title Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer
title_full Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer
title_fullStr Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer
title_full_unstemmed Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer
title_short Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer
title_sort human retrotransposons and the global shutdown of homeostatic innate immunity by oncolytic parvovirus h-1pv in pancreatic cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228339/
https://www.ncbi.nlm.nih.gov/pubmed/34071585
http://dx.doi.org/10.3390/v13061019
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