8th Euro Global Summit on Cancer Therapy
Hokkaido University, Japan Panel Discussion
Title: Tumor suppressive effect driven by cytoplasmic RNA-mediated innate signaling
Biography: Akinori Takaoka
The type I interferons (IFNs) including IFN-alphas and IFN-beta are innate cytokines that directly or indirectly regulates antiviral defense. Activation of pattern recognition receptor (PRR) by viral pathogen-associated molecular patterns (PAMPs) such as nucleic acids leads to massive production of IFN-alpha/beta, which confers cells with antiviral state in an IFNAR (IFN-alpha/betareceptor)- dependent manner. As well as eliciting strong antiviral activities, these cytokines are also known to show antitumor eff ect and immuno-modulating eff ect. In this study, we tried to harness cytoplasmic RNA-mediated activation of IFN pathway to directly suppress tumor growth. We fi rst found that among various cancer cell lines tested, human breast cancer MCF-7 cells robustly induced IFN-beta production in response to stimulation with 5’-triphosphate RNA and poly(rI:rC), both of which are synthetic ligands for cytoplasmic RNA sensors such as RIG-I and MDA5, respectively. In addition, MCF-7 cells were found to undergo signifi cant cell death in response to stimulation with these RLR ligands. Th is tumor cell death was suppressed by blockade of type I IFN signaling with anti-IFNAR-2 antibodies, suggesting that the RLR-ligand-induced cell death is dependent at least in part on type I IFN receptormediated signaling. Interestingly, in the absence of RLR ligand stimulation, IFN-beta treatment alone failed to remarkably induce tumor cell death. Consistent with this result, in vivo tumor growth of MCF-7 in nude mice was suppressed by treatment with RLR ligands but not IFN-beta. Th us, our present data suggest that the RLR-mediated signaling is essential to achieve the IFN-dependent cell death of MCF-7, and may provide a new insight into innate signaling-assisted cancer therapy.