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.

中文翻译：

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顺铂通过下调c-FLIP在恶性间皮瘤中释放Toll样受体3介导的凋亡。

Toll样受体3（TLR3）是一种免疫受体，其行为类似于肿瘤细胞中的死亡受体，从而为癌症治疗提供了原始靶标。迄今为止，尚未针对TLR3靶向治疗恶性间皮瘤（一种侵袭性和不可治愈的胸膜和腹膜瘤）的治疗潜力。我们调查了TLR3的表达和人类间皮瘤细胞系对合成的dsRNA Poly（I：C）的敏感性，单独或与顺铂联合使用，这是间皮瘤的金标准化疗。Poly（I：C）对TLR3的激活诱导了4/8 TLR3阳性细胞系的凋亡，但未诱导TLR3阴性细胞系的凋亡。联合使用顺铂/聚（I：C）处理可增强3/4 Poly（I：C）敏感细胞系的凋亡，并克服了2/4细胞系对单独的Poly（I：C）或顺铂的耐药性。联合治疗的有效性依赖于顺铂诱导的c-FLIP的下调，c-FLIP是外源性凋亡途径的主要调节剂，导致增强的caspase-8介导的途径。值得注意的是，从腹膜间皮瘤患者中分离出的6/6原代细胞样品表达了TLR3。患者来源的细胞对单独的Poly（I：C）敏感，而顺铂/ Poly（I：C）联合治疗可引起戏剧性的细胞死亡。我们的发现表明，TLR3靶向联合顺铂在间皮瘤中提出了一种创新的治疗策略。患者来源的细胞对单独的Poly（I：C）敏感，而顺铂/ Poly（I：C）联合治疗可引起戏剧性的细胞死亡。我们的发现表明，TLR3靶向联合顺铂在间皮瘤中提出了一种创新的治疗策略。患者来源的细胞对单独的Poly（I：C）敏感，而顺铂/ Poly（I：C）联合治疗可引起戏剧性的细胞死亡。我们的发现表明，TLR3靶向联合顺铂在间皮瘤中提出了一种创新的治疗策略。