Microbial Cell (Apr 2023)

TL-532, a novel specific Toll-like receptor 3 agonist rationally designed for targeting cancers: discovery process and biological characterization

  • Sylvain Thierry,
  • Sarah Maadadi,
  • Aurore Berton,
  • Laura Dimier,
  • Clémence Perret,
  • Nelly Vey,
  • Saïd Ourfali,
  • Mathilde Saccas,
  • Solène Caron,
  • Mathilde Boucard-Jourdin,
  • Marc Colombel,
  • Bettina Werle,
  • Marc Bonnin

DOI
https://doi.org/10.15698/mic2023.06.797
Journal volume & issue
Vol. 10, no. 06
pp. 117 – 132

Abstract

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Toll-like receptor 3 (TLR3) is an innate immune receptor that recognizes double-stranded RNA (dsRNA) and induces inflammation in immune and normal cells to initiate anti-microbial responses. TLR3 acts also as a death receptor only in cancer cells but not in their normal counterparts, making it an attractive target for cancer therapies. To date, all of the TLR3-activating dsRNAs used at preclinical or clinical stages have major drawbacks such as structural heterogeneity, toxicity, and lack of specificity and/or efficacy. We conducted the discovery process of a new family of TLR3 agonists that are chemically manufactured on solid-phase support and perfectly defined in terms of sequence and size. A stepwise discovery process was performed leading to the identification of TL-532, a 70 base pair dsRNA that is potent without transfection reagent and is highly specific for TLR3 without activating other innate nucleic sensors such as RIG-I/MDA5, TLR7, TLR8, and TLR9. TL-532 induces inflammation in murine RAW264.7 myeloid macrophages, in human NCI-H292 lung cancer cells, and it promotes immunogenic apoptosis in tumor cells in vitro and ex vivo without toxicity towards normal primary cells. In conclusion, we identified a novel TLR3 agonist called TL-532 that has promising anticancer properties.

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