High throughput screen identifies lysosomal acid phosphatase 2 (ACP2) to regulate IFN-1 responses to potentiate oncolytic VSV∆51 activity.

Autor: Wong B; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada., Birtch R; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada., Bergeron A; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada., Ng K; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada., Maznyi G; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada., Spinelli M; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada., Chen A; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada., Landry A; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada., Crupi MJF; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada., Arulanandam R; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada., Ilkow CS; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada., Diallo JS; Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. jsdiallo@ohri.ca.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. jsdiallo@ohri.ca.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Nov 16; Vol. 14 (1), pp. 28284. Date of Electronic Publication: 2024 Nov 16.
DOI: 10.1038/s41598-024-76855-3
Abstrakt: Strategies in genetic and pharmacological modulation of innate immunity to enhance oncolytic virotherapy (OV) efficacy are being explored. We have recently characterized the ability for vanadium-based compounds, a class of pan-phosphatase (PP) inhibitors, to potentiate OVs. We next sought to identify PPs that could be targeted to enhance OVs, akin to vanadium. By conducting a high-throughput screen of a library of silencing RNA (siRNA) targeting human PPs, we uncovered several PPs that robustly enhanced infectivity and oncolysis of the oncolytic vesicular stomatitis virus (VSV∆51). Knockdown of our top validated hit, lysosomal acid phosphatase 2 (ACP2), increased VSV∆51 viral titers by over 20-fold. In silico analysis by RNA sequencing revealed ACP2 to regulate antiviral type I interferon (IFN-1) signaling pathways, similar to vanadium. To further exploit this mechanism for therapeutic gain, we encoded a short-hairpin RNA (shRNA) against ACP2 into oncolytic vesicular stomatitis virus (VSV∆51) under a miR-30 promoter. This bioengineered OV demonstrated expression of the miR-30 promoter, knockdown of ACP2, repression and ultimately, showed markedly enhanced viral VSV∆51 particle production compared to its non-targeting control counterpart. Altogether, this study identifies IFN-1 regulating PP targets, namely ACP2, that may prove instrumental in increasing the therapeutic efficacy of OVs.
Competing Interests: Declarations Competing interests The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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