Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma. (1st March 2020)

• Record Type: Journal Article
• Authors: Vanbervliet-Defrance, Béatrice; Delaunay, Tiphaine; Daunizeau, Thomas; Kepenekian, Vahan; Glehen, Olivier; Weber, Kathrin; Estornes, Yann; Ziverec, Audrey; Djemal, Leila; Delphin, Marion; Lantuéjoul, Sylvie; Passot, Guillaume; Grégoire, Marc; Micheau, Olivier; Blanquart, Christophe; Renno, Toufic; Fonteneau, Jean-François; Lebecque, Serge; Mahtouk, Karène
• Is Part Of: Cancer letters. Volume 472(2020)
• Page Start: 29
• Page End: 39
• Publication Date: 2020-03-01
• Subjects: Mesothelioma -- Immune receptor -- Therapy -- Apoptosis -- Inflammation; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.12.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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 cisplatin-induced 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. Highlights: The immune receptor Toll-like receptor 3 is expressed on mesothelioma cell lines. The synthetic dsRNA Poly(I:C) induces apoptosis of mesothelioma cell lines. Cisplatin increases Poly(I:C)-mediated apoptosis and overcomes resistance. Cisplatin enhances caspase-8-mediated apoptosis pathway through c-FLIP downregulation. Patient-derived primary mesothelioma cells are efficiently killed by the cisplatin/Poly(I:C) combination.