免疫检查点致死性副作用的机制和个体化处理

Mechanism of Fatal Toxic Effect Associated with Immune Checkpoint Inhibitors and Its Individualized Management

近年来,免疫检查点抑制剂(immune checkpoint inhibitor,ICI)在肿瘤免疫治疗方面取得了巨大成功,但也因为脱靶(off-target)效应导致了全新的毒性谱。其中尤其是主要器官(包括心脏、肺和脑)的严重免疫相关不良事件(irAE)可能危及生命。已有数据表明ICI可能通过4种机制诱导脱靶效应,包括直接结合正常细胞表面表达的免疫检查点分子,激活补体超敏反应;正常组织与肿瘤细胞存在同源抗原/表位;产生自身抗体;增加前炎症细胞因子的水平。在了解癌症免疫治疗的毒性及其潜在机制后,对于典型逐步增加的免疫抑制药物(如皮质类固醇)方法,提出了一种新的个体化关闭策略,旨在抑制参与免疫相关不良事件病理生理过程的各种炎症成分,不仅阻断急性期的免疫炎症毒性,而且抑制由IL-1和IL-6等炎症因子促进的肿瘤发展。

In recent years,immune checkpoint inhibitor(ICI)has achieved great success in cancer immunotherapy,but it also leads to a new toxicity spectrum due to off-target effect.Severe immune-related adverse events(irAE)of major organs(including heart,lung and brain)may be lifethreatening.It has been shown that ICI can induce miss-target effects through direct binding of immunological checkpoint molecules expressed on the surface of normal cells and activation of complement hypersensitivity;homologous antigens/epitopes between normal tissues and cancer cells;generation of autoantibodies and increasing levels of pro-inflammatory cytokines.Based on understanding the toxicity of cancer immunotherapy and its potential mechanism,a new individualized closure strategy has been proposed for typical incremental immunosuppressive drugs(such as corticosteroids)to inhibit the various inflammatory components involved in the pathophysiological process of immune-related adverse events.It not only blocked the immuno-inflammatory toxicity in acute phase,but also inhibited the inflammation and cancer development caused by IL-1 and IL-6.