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Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer

Authors :
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
Nathalia A. Giese
Source :
Viruses, Vol 13, Iss 6, p 1019 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
19994915 and 45638411
Volume :
13
Issue :
6
Database :
Directory of Open Access Journals
Journal :
Viruses
Publication Type :
Academic Journal
Accession number :
edsdoj.5d5ce1a759fd45638411f8ab7d8bf8e3
Document Type :
article
Full Text :
https://doi.org/10.3390/v13061019