Breaking tumor-induced immunosuppression with 5'-triphosphate siRNA silencing TGFβ and activating RIG-I

Abstract

Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor that is activated by 5'-triphosphate RNA molecules to induce type I interferon secretion and apoptosis in response to viral infection. We have designed a bifunctional small-interfering RNA that combines transforming growth factor β silencing with RIG-I activation to break tumor-induced immunosuppression. This strategy showed therapeutic efficacy in a murine model of pancreatic cancer.

Keywords: RIG-I; TGFβ; immunosuppression; pancreatic cancer; siRNA.

Figure 1. Immune activation with a triphosphate small-interfering RNA targeting transforming growth factor β brakes tumor-induced immunosuppression. (A) A 5′-triphosphate-modified small-interfering RNA targeting transforming growth factor β (ppp-TGFβ) combines the potential of RNA-interference (RNAi)-mediated TGFβ silencing and that of retinoic acid-inducible gene I (RIG-I) activation, leading to the secretion of type I interferon (IFN) and other pro-inflammatory cytokines. (B) In vivo, the administration of ppp-TGFβ leads to the production of type I IFN and various chemokines (such as CXCL10), to the upregulation of MHC class I expression on tumor cells as well as to tumor cell apoptosis. Additionally, ppp-TGFβ favors the apoptotic demise of myeloid-derived suppressor cells (MDSCs), the recruitment of CD8⁺ T cells into neoplastic lesions, T_H1 polarization and cytotoxic T lymphocyte (CTL) activation in a murine model of pancreatic carcinoma.