Reschke Robin, Sullivan Ryan J, Lipson Evan J, Enk Alexander H, Gajewski Thomas F, Hassel Jessica C
Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Core Center Heidelberg, 69120 Heidelberg, Germany.
Mass General Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
Trends Immunol. 2025 Jan;46(1):61-73. doi: 10.1016/j.it.2024.11.014. Epub 2024 Dec 27.
Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are frequently associated with immune-related adverse events (irAEs). This article offers a novel synthesis of findings from both preclinical and clinical studies, focusing on the molecular mechanisms driving irAEs across diverse organ systems. It examines key immune cells, such as T cell subsets and myeloid cells, which are instrumental in irAE pathogenesis, alongside an in-depth analysis of cytokine signaling [interleukin (IL)-6, IL-17, IL-4), interferon γ (IFN-γ), IL-1β, tumor necrosis factor α (TNF-α)], integrin-mediated interactions [integrin subunits αITGA)4 and ITGB7], and microbiome-related factors that contribute to irAE pathology. This exploration of modifiable pathways uncovers new opportunities to mitigate irAEs by using available antibodies (Abs) that target key inflammatory molecules across tumor types, while ideally preserving the antitumor efficacy of ICIs.
免疫检查点抑制剂（ICIs）已经改变了癌症治疗方式，但常常与免疫相关不良事件（irAEs）相关联。本文对临床前和临床研究的结果进行了新颖的综合分析，重点关注驱动不同器官系统中irAEs的分子机制。它研究了关键免疫细胞，如T细胞亚群和髓样细胞，这些细胞在irAE发病机制中起重要作用，同时深入分析了细胞因子信号传导[白细胞介素（IL）-6、IL-17、IL-4、干扰素γ（IFN-γ）、IL-1β、肿瘤坏死因子α（TNF-α）]、整合素介导的相互作用[整合素亚基α4（ITGA4）和β7（ITGB7）]以及与微生物群相关的因素，这些因素都对irAE病理产生影响。对可调节途径的这一探索揭示了通过使用针对不同肿瘤类型关键炎症分子的现有抗体（Abs）来减轻irAEs的新机会，同时理想地保留ICIs的抗肿瘤疗效。
