Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783712720016637952 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8228339 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT neulingermunozmatthias humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT schaackdominik humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT grekovasvetlanap humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT bauerandreas humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT giesethomas humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT salggabriela humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT espinetelisa humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT leuchsbarbara humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT helleranette humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT nueschjurgpf humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT schenkmiriam humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT volkmarmichael humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer AT giesenathaliaa humanretrotransposonsandtheglobalshutdownofhomeostaticinnateimmunitybyoncolyticparvovirush1pvinpancreaticcancer |