Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory "checkpoint" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.

中文翻译：

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是时候剖析癌症抗体免疫疗法的自身免疫病因了。

免疫疗法改变了多种人类癌症的治疗格局。免疫检查点抑制剂 (ICIs) 是阻断免疫调节“检查点”受体 CTLA-4、PD-1 或​​其配体 PD-L1 的单克隆抗体，可以在某些患者中产生持久的反应。然而，在取得成功的同时，这些治疗通常会引发一系列与免疫相关的不良事件 (irAE)，这些不良事件可能会影响任何器官系统，并可能限制治疗并危及生命，例如糖尿病酮症酸中毒，这似乎更严重。比最初描述的更频繁。检查点封锁引起的大多数 irAE 涉及屏障组织（例如胃肠粘膜或皮肤）或内分泌器官，尽管任何器官系统都可能受到影响。通常，irAE 类似于自发性自身免疫性疾病，例如炎症性肠病、自身免疫性甲状腺疾病、1 型糖尿病 (T1D) 和自身免疫性胰腺炎。然而，目前尚不清楚这些明显的自身免疫不良事件和经典自身免疫疾病是否存在相似的分子或病理机制。有趣的是，有证据表明 HLA 等位基因与 ICI 诱发的 T1D 和结肠炎的自身免疫性疾病高风险相关。了解驱动 ICI 介导的炎症毒性的遗传风险和免疫机制不仅可以确定可用于管理 irAE 的治疗靶点，还可以为自身免疫性疾病的病理学和治疗提供新的见解。