Year-end Sale % OFF 
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.
Highlights
The oncolytic parvovirus H-1PV has already entered clinical trials targeting glioblastoma and pancreatic cancer [1,2], but curing protocols are yet to be generated.A promising way to achieve this goal is the induction of the immunogenic form of cell death (ICD), which efficiently couples oncolysis with immune activation triggering longterm anticancer responses [3]
To explore the relationship between H-1PV and innate immunity in pancreatic cancer, we infected nine PDAC cell lines and monitored the expression of three marker interferon-stimulated genes (ISG) (ISG15, IFITM1, OAS1) and three marker Human Endogenous Retroviruses (HERV) known for establishing an antiviral state in tumor cells (HERV-K env, HERV-W env, HERV-W pol) [43]
Our study demonstrates that in contrast to immune cells, tumor cells fail to recognize early parvoviral intermediates
Summary
A promising way to achieve this goal is the induction of the immunogenic form of cell death (ICD), which efficiently couples oncolysis with immune activation triggering longterm anticancer responses [3]. In pancreatic cancer (PDAC), the lack of complete tumor eradication might be due to the restricted ability of H-1PV to fully induce ICD. 1 (HMGB1) and, at least partially, ATP but not the translocation of calreticulin to the cell surface (ecto-CALR) [9]. Since the function of the latter was recently reassigned from an “eat-me” signal to type I interferon (IFN-I) triggering, the ecto-CALR-independent induction of IFN emerged as an alternative route to achieve ICD and promote the desired
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
