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Updated: Jun 7, 2025
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
High throughput screen identifies lysosomal acid phosphatase 2 (ACP2) to regulate IFN-1 responses to potentiate
Boaz Wong1,2, Rayanna Birtch1,2, Anabel Bergeron1,2
1Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.
Abstract:
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.
Insights
Researchers identified lysosomal acid phosphatase 2 (ACP2) as a key target to enhance oncolytic virotherapy (OV). Inhibiting ACP2 boosts viral replication and oncolysis, offering a new strategy for cancer treatment.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Strategies to enhance oncolytic virotherapy (OV) efficacy by modulating innate immunity are under investigation.
- Vanadium compounds, known pan-phosphatase (PP) inhibitors, have shown potential to potentiate OVs.
Purpose of the Study:
- To identify novel pan-phosphatase (PP) targets for enhancing OV efficacy.
- To investigate the role of lysosomal acid phosphatase 2 (ACP2) in potentiating oncolytic vesicular stomatitis virus (VSV∆51).
Main Methods:
- High-throughput screening of a small interfering RNA (siRNA) library targeting human PPs.
- RNA sequencing for in silico analysis of ACP2's role in antiviral signaling.
- Bioengineering of VSV∆51 to express short hairpin RNA (shRNA) against ACP2.
Main Results:
- Lysosomal acid phosphatase 2 (ACP2) was identified as a key target that enhances VSV∆51 infectivity and oncolysis.
- ACP2 knockdown increased VSV∆51 viral titers over 20-fold.
- Engineered VSV∆51 expressing shRNA against ACP2 demonstrated significantly enhanced viral particle production.
Conclusions:
- ACP2 regulates type I interferon (IFN-1) signaling pathways, similar to vanadium.
- Targeting ACP2 represents a promising strategy to improve the therapeutic efficacy of oncolytic virotherapy.
