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

Nat Commun. 2015 Feb 18;6:6280. doi: 10.1038/ncomms7280.

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.

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Adjuvants, Immunologic / chemistry*
  • Animals
  • Cytokines / metabolism
  • Dendritic Cells / cytology
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Inflammation
  • Killer Cells, Natural / cytology*
  • Ligands
  • Lymphocyte Activation / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Transplantation
  • Phosphorothioate Oligonucleotides / chemistry
  • Poly I-C / chemistry
  • RNA / chemistry*
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic / cytology*
  • Toll-Like Receptor 3 / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Adjuvants, Immunologic
  • Cytokines
  • Ligands
  • Phosphorothioate Oligonucleotides
  • TICAM-1 protein, mouse
  • TICAM1 protein, human
  • TLR3 protein, human
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • RNA
  • Poly I-C