siRNA-induced immunostimulation through TLR7 promotes antitumoral activity against HPV-driven tumors in vivo View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-02

AUTHORS

Norliana Khairuddin, Michael P Gantier, Stephen J Blake, Sherry Y Wu, Mark A Behlke, Bryan RG Williams, Nigel AJ McMillan

ABSTRACT

Oncogene-specific downregulation mediated by RNA interference (RNAi) is a promising avenue for cancer therapy. In addition to specific gene silencing, in vivo RNAi treatment with short interfering RNAs (siRNAs) can initiate immune activation through innate immune receptors including Toll-like receptors, (TLRs) 7 and 8. Two recent studies have shown that activation of innate immunity by addition of tri-phosphate motifs to oncogene-specific siRNAs, or by co-treatment with CpG oligos, can potentiate siRNA antitumor effects. To date, there are no reports on applying such approach against human papillomavirus (HPV)-driven cancers. Here, we characterized the antitumor effects of non-modified siRNAs that can target a specific oncogene and/or recruit the innate immune system against HPV-driven tumors. Following the characterization of silencing efficacy and TLR7 immunostimulatory potential of 15 siRNAs targeting the HPV type 16 E6/E7 oncogenes, we identified a bifunctional siRNA sequence that displayed both potent gene silencing and active immunostimulation effect. In vivo systemic administration of this siRNA resulted in reduced growth of established TC-1 tumors in C57BL/6 mice. Ablation of TLR7 recruitment via 2'O-methyl modification of the oligo backbone reduced these antitumor effects. Further, a highly immunostimulatory, but non-HPV targeting siRNA was also able to exert antitumoral effects although for less prolonged time compared with the bifunctional siRNA. Collectively, our work demonstrates for the first time that siRNA-induced immunostimulation can have antitumoral effects against HPV-driven tumors in vivo, even independent of gene silencing efficacy. More... »

PAGES

187

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/icb.2011.19

    DOI

    http://dx.doi.org/10.1038/icb.2011.19

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1033123913

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/21423261


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