Introduction. Poly(I:C) is a synthetic analogue of double-stranded RNA that signals via TLR3, and other RNA sensing pathways. Poly (I:C) has been described as a powerful inducer of type I interferon (IFN), in particular IFNb, and has been used as an anti-cancer therapy; however, the biological mechanism of action is not well understood.
Problem Statement. In this study, we aimed to assess the downstream biological mechanism of action of poly (I:C), which would shape further studies for therapeutic use.
Methods. Mice with subcutaneous tumours were treated with intra-tumoural poly(I:C). Following treatment, we assessed the cellular uptake of fluorescein-labelled poly(I:C) and analysed changes in the immune cell populations within the tumour microenvironment. We used bulk RNAseq to map the transcriptomic changes over the course of treatment and performed differential gene expression and pathway analyses. In vivo cytokine blocking and cell depletion experiments were used to validate the bioinformatics findings.
Results. Poly (I:C) was taken up predominately by intra-tumoural macrophages and induced an IFN α/β-related transcriptomic profile. Blocking the interferon α/β receptor (IFNAR1) or IFNα itself completely abolished the anti-tumour response whereas, surprisingly, blocking IFNβ had no effect. Local administration of poly (I:C) depleted Tregs and attracted inflammatory monocytes in the tumour, which was completely abrogated by IFNAR1 blockade. Depletion of CD8+ but not CD4+ T cells significantly reduced the efficacy of local poly(I:C).
Conclusion. Taken together, these data demonstrate that the anti-tumour efficacy of poly (I:C) is IFNα-dependent, resulting in depletion of Tregs and recruitment of inflammatory monocytes in the tumour microenvironment and that CD8+ T cells are essential for the poly (I:C)-induced anti-tumour effect.