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

• Published in: Microbial cell 2023-06, Vol.10 (6), p.117-132
• Main Authors: Thierry, Sylvain, Maadadi, Sarah, Berton, Aurore, Dimier, Laura, Perret, Clémence, Vey, Nelly, Ourfali, Saïd, Saccas, Mathilde, Caron, Solène, Boucard-Jourdin, Mathilde, Colombel, Marc, Werle, Bettina, Bonnin, Marc
• Format: Article
• Language: English
• Subjects: Agonist; Apoptosis; Cancer Therapy; Inflammation; Toll-like Receptor 3
• ISSN: 2311-2638; 2311-2638
• DOI: 10.15698/mic2023.06.797

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 and without toxicity towards normal primary cells. In conclusion, we identified a novel TLR3 agonist called TL-532 that has promising anticancer properties.