SiRNA-induced immunostimulation through TLR7 promotes antitumoral activity against HPV-driven tumors in vivo

Norliana Khairuddin, Michael P. Gantier, Stephen J. Blake, Sherry Y. Wu, Mark A. Behlke, Bryan Rg Williams, Nigel Aj McMillan

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)187-196
Number of pages10
JournalImmunology and cell biology
Volume90
Issue number2
DOIs
Publication statusPublished - 1 Feb 2012

Keywords

  • HPV16 E6/E7
  • RNAi
  • TLR7
  • bifunctional siRNA
  • dicer-substrate siRNA
  • immunostimulation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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