In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours

Norliana Khairuddin, Stephen Blake, Farah Firdaus, Raymond J Steptoe, Mark A Behlke, Paul John Hertzog, Nigel A J McMillan

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8 Citations (Scopus)

Abstract

Small interfering RNAs (siRNAs) to inhibit oncogene expression and also to activate innate immune responses via Toll-like receptor (TLR) recognition have been shown to be beneficial as anti-cancer therapy in certain cancer models. In this study, we investigated the effects of local versus systemic delivery of such immune-stimulating Dicer-substrate siRNAs (IS-DsiRNAs) on a human papillomavirus (HPV)-driven tumour model. Localized siRNA delivery using intratumour injection of siRNA was able to increase siRNA delivery to the tumour compared with intravenous (IV) delivery and potently activated innate immune responses. However, IV injection remained the more effective delivery route for reducing tumour growth. Although IS-DsiRNAs activated innate immune cells and required interferon-alpha (IFNalpha) for full effect on tumour growth, we found that potent silencing siRNA acting independently of IFNalpha were overall more effective at inhibiting TC-1 tumour growth. Other published work utilising IS-siRNAs have been carried out on tumour models with low levels of major histocompatibility complex (MHC)-class 1, a target of natural killer cells that are potently activated by IS-siRNA. As TC-1 cells used in our study express high levels of MHC-class I, the addition of the immunostimulatory motifs may not be as beneficial in this particular tumour model. Our data suggest that selection of siRNA profile and delivery method based on tumour environment is crucial to developing siRNA-based therapies.
Original languageEnglish
Pages (from-to)156 - 163
Number of pages8
JournalImmunology and Cell Biology
Volume92
Issue number2
DOIs
Publication statusPublished - 2014

Cite this

Khairuddin, N., Blake, S., Firdaus, F., Steptoe, R. J., Behlke, M. A., Hertzog, P. J., & McMillan, N. A. J. (2014). In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours. Immunology and Cell Biology, 92(2), 156 - 163. https://doi.org/10.1038/icb.2013.75
Khairuddin, Norliana ; Blake, Stephen ; Firdaus, Farah ; Steptoe, Raymond J ; Behlke, Mark A ; Hertzog, Paul John ; McMillan, Nigel A J. / In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours. In: Immunology and Cell Biology. 2014 ; Vol. 92, No. 2. pp. 156 - 163.
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abstract = "Small interfering RNAs (siRNAs) to inhibit oncogene expression and also to activate innate immune responses via Toll-like receptor (TLR) recognition have been shown to be beneficial as anti-cancer therapy in certain cancer models. In this study, we investigated the effects of local versus systemic delivery of such immune-stimulating Dicer-substrate siRNAs (IS-DsiRNAs) on a human papillomavirus (HPV)-driven tumour model. Localized siRNA delivery using intratumour injection of siRNA was able to increase siRNA delivery to the tumour compared with intravenous (IV) delivery and potently activated innate immune responses. However, IV injection remained the more effective delivery route for reducing tumour growth. Although IS-DsiRNAs activated innate immune cells and required interferon-alpha (IFNalpha) for full effect on tumour growth, we found that potent silencing siRNA acting independently of IFNalpha were overall more effective at inhibiting TC-1 tumour growth. Other published work utilising IS-siRNAs have been carried out on tumour models with low levels of major histocompatibility complex (MHC)-class 1, a target of natural killer cells that are potently activated by IS-siRNA. As TC-1 cells used in our study express high levels of MHC-class I, the addition of the immunostimulatory motifs may not be as beneficial in this particular tumour model. Our data suggest that selection of siRNA profile and delivery method based on tumour environment is crucial to developing siRNA-based therapies.",
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Khairuddin, N, Blake, S, Firdaus, F, Steptoe, RJ, Behlke, MA, Hertzog, PJ & McMillan, NAJ 2014, 'In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours', Immunology and Cell Biology, vol. 92, no. 2, pp. 156 - 163. https://doi.org/10.1038/icb.2013.75

In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours. / Khairuddin, Norliana; Blake, Stephen; Firdaus, Farah; Steptoe, Raymond J; Behlke, Mark A; Hertzog, Paul John; McMillan, Nigel A J.

In: Immunology and Cell Biology, Vol. 92, No. 2, 2014, p. 156 - 163.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Khairuddin, Norliana

AU - Blake, Stephen

AU - Firdaus, Farah

AU - Steptoe, Raymond J

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AU - Hertzog, Paul John

AU - McMillan, Nigel A J

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