Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo

Misako Matsumoto (), Megumi Tatematsu, Fumiko Nishikawa, Masahiro Azuma, Noriko Ishii, Akiko Morii-Sakai, Hiroaki Shime and Tsukasa Seya ()
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Misako Matsumoto: Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku
Megumi Tatematsu: Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku
Fumiko Nishikawa: Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku
Masahiro Azuma: Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku
Noriko Ishii: Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku
Akiko Morii-Sakai: Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku
Hiroaki Shime: Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku
Tsukasa Seya: Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Ligand stimulation of the Toll-like receptors (TLRs) triggers innate immune response, cytokine production and cellular immune activation in dendritic cells. However, most TLR ligands are microbial constituents, which cause inflammation and toxicity. Toxic response could be reduced for secure immunotherapy through the use of chemically synthesized ligands with defined functions. Here we create an RNA ligand for TLR3 with no ability to activate the RIG-I/MDA5 pathway. This TLR3 ligand is a chimeric molecule consisting of phosphorothioate ODN-guided dsRNA (sODN-dsRNA), which elicits far less cytokine production than poly(I:C) in vitro and in vivo. The activation of TLR3/TICAM-1 pathway by sODN-dsRNA effectively induces natural killer and cytotoxic T cells in tumour-loaded mice, thereby establishing antitumour immunity. Systemic cytokinemia does not occur following subcutaneous or even intraperitoneal administration of sODN-dsRNA, indicating that TICAM-1 signalling with minute local cytokines sufficiently activate dendritic cells to prime tumoricidal effectors in vivo.

Date: 2015
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DOI: 10.1038/ncomms7280

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