Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies
Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies
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DOI：
10.3390/jcm8060762
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发表时间：
2019-06-01
影响因子：
3.9
通讯作者：
Sakagami, Takuro
中科院分区：
文献类型：
--
作者：
Sato, Ryo;Imamura, Kosuke;Sakagami, Takuro
免疫检查点的破坏会导致免疫稳态的失衡，导致免疫相关的不良事件。最近的病例研究表明，免疫检查点抑制物(ICIS)与凝血-纤溶系统的紊乱有关，这意味着全身免疫激活可能会影响凝血和出血之间的平衡。然而，凝血-纤溶系统紊乱与ICIS疗效之间的关系却知之甚少。我们对熊本大学医院接受ICI治疗的83名肺癌患者进行了回顾性评估。临床结果和与凝血-纤溶系统紊乱相关的疾病与肿瘤PD-L1表达的相关性被评估。83例非小细胞肺癌患者中，10例(12%)出现与凝血-纤溶系统紊乱有关的疾病。我们发现PD-L1高表达的患者在ICI开始的早期就出现了凝血-纤溶系统的紊乱。此外，观察到高肿瘤反应(72%)，包括这些患者中的两个完全反应。此外，在体外，我们证明T细胞激活强烈地诱导外周PD-L1(高)单核细胞产生凝血的主要起始物--组织因子。这项研究表明，在ICI治疗期间，免疫激活在触发癌症患者凝血-纤溶系统紊乱方面发挥了先前不为人知的关键作用。
A disruption of immune checkpoints leads to imbalances in immune homeostasis, resulting in immune-related adverse events. Recent case studies have suggested the association between immune checkpoint inhibitors (ICIs) and the disorders of the coagulation-fibrinolysis system, implying that systemic immune activation may impact a balance between clotting and bleeding. However, little is known about the association of coagulation-fibrinolysis system disorder with the efficacy of ICIs. We retrospectively evaluated 83 lung cancer patients who received ICI at Kumamoto University Hospital. The association between clinical outcome and diseases associated with disorders of the coagulation-fibrinolysis system was assessed along with tumor PD-L1 expression. Among 83 NSCLC patients, total 10 patients (12%) developed diseases associated with the disorder of coagulation-fibrinolysis system. We found that disorders of the coagulation-fibrinolysis system occurred in patients with high PD-L1 expression and in the early period of ICI initiation. In addition, high tumor responses (72%) were observed, including two complete responses among these patients. Furthermore, we demonstrate T-cell activation strongly induces production of a primary initiator of coagulation, tissue factor in peripheral PD-L1(high) monocytes, in vitro. This study suggests a previously unrecognized pivotal role for immune activation in triggering disorders of the coagulation-fibrinolysis system in cancer patients during treatment with ICI.