在接受免疫检查点抑制剂 (ICIs) 治疗的黑色素瘤患者中，高达 60% 的患者会出现以靶向炎症为特征的免疫相关不良事件 (irAE)。有证据证明，有严重 irAE 发展风险的患者的基线外周血谱与临床自身免疫相似。对于患有自身免疫性疾病（例如自身免疫性结肠炎）的病例，建议使用 risankizumab 阻断白细胞介素 (IL)-23。然而，目前，IL-23在irAE发病和严重程度中的作用仍知之甚少。基于GSE186143数据集的回顾性分析确定了与严重irAE发病最相关的促炎细胞因子。为了研究预防性IL-23阻断给药对预防irAEs的功效，参考之前的研究，我们构建了两种irAEs小鼠模型，包括葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型和联合ICIs诱导的irAEs小鼠模型模型。为了进一步探讨我们的研究结果的适用性，建立了移植物抗宿主病小鼠模型，其中用人外周血单核细胞移植 Rag2-/-Il2rg-/- 小鼠并接受联合细胞毒性 T 淋巴细胞相关抗原 4 (CTLA-4) 和程序性细胞死亡蛋白-1 (PD-1) 治疗。同时将人类黑色素瘤细胞异种移植到这些小鼠体内。在这里，我们发现，在接受抗 CTLA-4 和抗 PD-1 双重治疗后，患有 irAE 的患者血清中 IL-23 上调，并且随着 irAE 严重程度的增加而增加。此外，增强型 CD4 Tem 可能优先成为 irAE 发病的基础。用抗小鼠 IL-23 抗体联合 CTLA-4 和 PD-1 免疫疗法治疗小鼠可改善结肠炎，此外还能保留抗肿瘤功效。此外，在患有 irAE 的异种移植小鼠模型中，使用临床可用的 IL-23 抑制剂（risankizumab）预防性阻断人 IL-23 可改善结肠炎、肝炎和肺部炎症，此外，保留了对肿瘤的免疫治疗控制。最后，我们还提供了一种基于两种基于血液的特征（IL-23 和 CD4 Tems）的新颖的基于机器学习的计算框架，该框架可能具有预测严重 irAE 和 ICI 反应的潜力。我们的研究不仅提供了临床上可行的分离策略不仅研究了联合 ICI 用于癌症免疫治疗的疗效和毒性，而且还开发了一种基于血液的生物标志物，使实现直接、非侵入性的检测分析成为可能，以早期预测 irAE 发病。© 作者（或他们的雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood.The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2-/-Il2rg-/- mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly.Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features-IL-23 and CD4+ Tems-that may have predictive potential for severe irAEs and ICIs response.Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.