Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma

Béatrice Vanbervliet-Defrance (1) , Tiphaine Delaunay (2, 3) , Thomas Daunizeau (1) , Vahan Kepenekian (4, 5) , Olivier Glehen (4, 5) , Kathrin Weber (1) , Yann Estornes (1) , Audrey Ziverec (1) , Leila Djemal (1) , Marion Delphin (1) , Sylvie Lantuéjoul (6, 7) , Guillaume Passot (4, 5) , Marc Grégoire (2, 3) , Olivier Micheau (8) , Christophe Blanquart (2, 3) , Toufic Renno (1) , Jean-François Fonteneau (2, 3) , Serge Lebecque (1, 9) , Karène Mahtouk (1)

1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 CRCINA-ÉQUIPE 4 - Immunogenic Cell Death and Mesothelioma Therapy
3 LabEX IGO Immunothérapie Grand Ouest
4 Centre Hospitalier Lyon Sud [CHU - HCL] CHLS - Service de Chirurgie Viscérale et Oncologique
5 EA3738 - Ciblage thérapeutique en Oncologie
6 Centre Léon Bérard [Lyon]
7 Fondation Synergie Lyon Cancer [Lyon]
8 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
9 Centre Hospitalier Lyon Sud [CHU - HCL] CHLS - Service D'Anatomie Pathologique

Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly (I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma. Activation of TLR3 by Poly(I:C) induced apoptosis of 4/8 TLR3-positive cell lines but not of TLR3-negative cell lines. The combined cisplatin/Poly(I:C) treatment enhanced apoptosis of 3/4 Poly(I:C)-sensitive cell lines and overcame resistance to Poly(I:C) or cisplatin alone in 2/4 cell lines. Efficacy of the combined treatment relied on cisplatininduced downregulation of c-FLIP, the main regulator of the extrinsic apoptotic pathway, leading to an enhanced caspase-8-mediated pathway. Of note, 6/6 primary cell samples isolated from patients with peritoneal mesothelioma expressed TLR3. Patient-derived cells were sensitive to Poly(I:C) alone while the combined cisplatin/Poly(I:C) treatment induced dramatic cell death. Our findings demonstrate that TLR3 targeting in combination with cisplatin presents an innovative therapeutic strategy in mesothelioma.

Keywords: Apoptosis; Immune receptor; Inflammation; Mesothelioma; Therapy

Domains: Cancer

Béatrice Vanbervliet-Defrance, Tiphaine Delaunay, Thomas Daunizeau, Vahan Kepenekian, Olivier Glehen, et al.. Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma. Cancer Letters, 2019, 472, pp.29-39. ⟨10.1016/j.canlet.2019.12.016⟩. ⟨inserm-02447216⟩