The TLR3 L412F polymorphism prevents TLR3-mediated tumor cell death induction in pediatric sarcomas

Author:

Bisaccia JosephORCID,Meyer SwannORCID,Bertrand-Chapel AdrienORCID,Hecquet Quentin,Barbet Virginie,Kaniewski Bastien,Léon Sophie,Gadot Nicolas,Rochet Isabelle,Fajnorova IvetaORCID,Leblond Pierre,Cordier-Bussat Martine,Corradini Nadège,Vasiljevic Alexandre,Billaud Marc,Picard Cécile,Broutier Laura,Gallerne Cindy,Dutour Aurélie,Blay Jean-YvesORCID,Castets MarieORCID

Abstract

AbstractToll-like receptor 3 (TLR3) is a pattern recognition receptor mainly known for its role in innate immune response to infection. Indeed, binding of double-stranded RNA (dsRNA) to TLR3 triggers a pro-inflammatory cascade leading to cytokine release and immune cell activation. Its anti-tumoral potential has emerged progressively, associated with a direct impact on tumor cell death induction and with an indirect action on immune system reactivation. Accordingly, TLR3 agonists are currently being tested in clinical trials for several adult cancers. Meanwhile, TLR3 variants have been linked to auto-immune disorders, and as risk factors of viral infection and cancers. However, aside from neuroblastoma, TLR3 role in childhood cancers has not been evaluated. Here, by integrating public transcriptomic data of pediatric tumors, we unveil that high TLR3 expression is largely associated with a better prognosis in childhood sarcomas. Using osteosarcomas and rhabdomyosarcomas as models, we show that TLR3 efficiently drives tumor cell death in vitro and induces tumor regression in vivo. Interestingly, this anti-tumoral effect was lost in cells expressing the homozygous TLR3 L412F polymorphism, which is enriched in a rhabdomyosarcomas cohort. Thus, our results demonstrate the therapeutic potential associated with the targeting of TLR3 in pediatric sarcomas, but also the need to stratify patients eligible for this clinical approach with respect to the TLR3 variants expressed.

Funder

Ligue Contre le Cancer

Fondation ARC pour la Recherche sur le Cancer

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology

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