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In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV‐driven tumours
Author(s) -
Khairuddin Norliana,
Blake Stephen J,
Firdaus Farah,
Steptoe Raymond J,
Behlke Mark A,
Hertzog Paul J,
McMillan Nigel AJ
Publication year - 2014
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2013.75
Subject(s) - small interfering rna , dicer , innate immune system , gene silencing , cancer research , immune system , biology , interferon , mhc class i , oncogene , rna interference , immunology , cancer , transfection , major histocompatibility complex , rna , cell culture , cell cycle , biochemistry , genetics , gene
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‐α (IFNα) for full effect on tumour growth, we found that potent silencing siRNA acting independently of IFNα 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.