Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas
Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas
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DOI：
10.1016/j.humpath.2016.01.010
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发表时间：
2016-06-01
期刊：
影响因子：
3.3
通讯作者：
Lantuejoul, Sylvie
中科院分区：
文献类型：
--
作者：
Combaz-Lair, Christelle;Galateau-Salle, Francoise;Lantuejoul, Sylvie
恶性胸膜间皮瘤（MPM）是一种侵袭性肿瘤，目前尚无有效的治疗方法。然而，PD-L1/PD-1免疫检查点疗法给出了令人鼓舞的结果; TLR 3是一种程序性死亡因子，其触发上调PD-L1。由于PD-1/PD-L1阻断抗体可以单独或与TLR 3激动剂组合恢复抗肿瘤免疫应答，我们研究了MPM中的PD-L1/PD-1和TLR 3表达以选择用于免疫治疗的患者。研究了68例胸膜手术标本，包括58例MPM（上皮样，n = 34;双相，n = 11;肉瘤样，n = 13）和10例良性病变。使用肿瘤细胞（TC）和肿瘤浸润淋巴细胞（TIL）中的E1 L3 N和SP142克隆评估PD-L1表达（阳性阈值为1%），并与总生存期进行比较。同时分析TIL的PD-1、CD 3和CD 8表达以及TC的TLR 3表达。PD-L1在肉瘤样亚型中的表达高于其他MPM（E1 L3 N为62% vs 23%和9%; SP142为38% vs 11%）（P分别为0.01和0.04）。E1 L3 N和SP142的特异性和敏感性分别为53%和98%，90%和86%。TIL和TC的PD-L1表达与SP142相关（P = .023），TC的PD-L1 SP142表达与较短的总生存期相关（P = .016）。TLR 3在大多数MPM中表达，而在肉瘤样MPM中表达较弱。我们通过比较两种市售抗体证实，肉瘤样MPM中PD-L1表达更高，并与较短的生存期相关。尽管可以在表达TLR 3的MPM中测试TLR 3激动剂，但是肉瘤样亚型可以受益于单独或组合的抗PD-L1/PD-1疗法。(C)2016 Elsevier Inc. All rights reserved.
Malignant pleural mesothelioma (MPM) is an aggressive tumor with no effective therapy. However PD-L1/PD-1 immunity checkpoint therapies gave encouraging results; TLR3 is a programmed death factor, which triggering up-regulates PD-L1. As PD-1/PD-L1 blocking antibodies could restore antitumor immune responses alone or in combination with TLR3 agonists, we investigated PD-L1/PD-1 and TLR3 expressions in MPM to select patients for immunotherapy. Sixty-eight pleural surgical specimens, including 58 MPM (epithelioid, n = 34; biphasic, n = 11; sarcomatoid, n = 13) and 10 benign lesions, were studied. PD-L1 expression was assessed using E1L3N and SP142 clones in tumor cells (TCs) and in tumor-infiltrating lymphocytes (TILs) (positivity threshold of 1%), and compared with overall survival. PD-1, CD3 and CD8 expression by TILs, and TLR3 expression by TCs were analyzed concomitantly. PD-L1 was more expressed by sarcomatoid subtype than by other MPM (62% versus 23% and 9% for E1L3N; 38% versus 11% for SP142) (P = .01 and .04, respectively). Specificity and sensitivity of E1L3N and SP142 were of 53% and 98%, and 90% and 86%, respectively. PD-L1 expression by TILs and TCs correlated for SP142 (P = .023), and PD-Ll SP142 expression by TCs was associated with shorter overall survival (P = .016). TLR3 was expressed in most MPM, but weakly in sarcomatoid MPM. We confirm by comparing two commercially available antibodies that PD-L1 expression is higher in sarcomatoid MPM and correlates with a shorter survival. Whereas TLR3 agonists could be tested in MPM expressing TLR3, the sarcomatoid subtype could benefit from anti PD-L1/PD-1 therapies alone or in combination. (C) 2016 Elsevier Inc. All rights reserved.