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Immunotherapy

CpG–siRNA deals double blow to tumours

Nature Reviews Immunology volume 9, page 753 (2009)Cite this article

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The authors coupled siRNA that targets signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor, to TLR9-specific CpG oligodeoxynucleotides, which are currently in clinical trials for the treatment of cancer, including melanoma. STAT3 has been shown to orchestrate the expression of immunosuppressive and angiogenic factors, contributing to a tumour environment characterized by a lack of tumour-specific cytotoxic T cells, an inhibition of T helper 1 (TH1) cells and an excess of regulatory T cells, as well as infiltration by myeloid-derived suppressor cells. STAT3 is also persistently activated in many tumour cells of diverse origin, which enhances tumour growth and survival and confers resistance to anticancer therapies. Furthermore, STAT3 is known to attenuate TLR-mediated TH1-type antitumour responses.

In several mouse models of cancer, peritumoural injection of the CpG–siRNA construct resulted in internalization of the construct by tumour-associated myeloid cells, as well as dendritic cells, macrophages and B cells in tumour-draining lymph nodes. Compared with CpG alone or CpG conjugated to random-sequence siRNA, the CpG–siRNA construct inhibited the growth of subcutaneous B16 and K1735 melanoma cells and CT26 colon carcinoma cells to a greater extent, and induced tumour regression in three out of four mice in the MC38 colon carcinoma model.

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ORIGINAL RESEARCH PAPER

  1. Kortylewski, M. et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumour immune responses. Nature Biotech. 27, 925–932 (2009).

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  1. Senior Editor, Nature Reviews Drug Discovery,

    Alexandra Flemming

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  1. Alexandra Flemming
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Flemming, A. CpG–siRNA deals double blow to tumours. Nat Rev Immunol 9, 753 (2009). https://doi.org/10.1038/nri2665

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  • DOI: https://doi.org/10.1038/nri2665

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