In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours.
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.
1] The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia [2] Immunotherapeutics Laboratory (ITL) and Centre of Excellence for Research in AIDS (CERiA), Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Norliana
N
Khairuddin
The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.
Stephen J
SJ
Blake
The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.
Farah
F
Firdaus
The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.
Raymond J
RJ
Steptoe
Integrated DNA Technologies (IDT), Coralville, IA, USA.
Mark A
MA
Behlke
Monash Institute of Medical Research (MIMR), Clayton, Victoria, Australia.
Paul J
PJ
Hertzog
1] The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia [2] School of Medical Science and Griffith Health Institute, Griffith University, Southport, Queensland, Australia.
Nigel A J
NA
McMillan
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D052685:Alphapapillomavirus / Q000276:immunology*; D000818:Animals; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D014412:Tumor Virus Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
D000276:Adjuvants, Immunologic; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; D034741:RNA, Small Interfering