神经免疫相关不良事件（irAE-n）很少见，但免疫检查点抑制剂（ICI）治疗的严重毒性。为了克服诊断和治疗挑战，更好地了解 irAE-n 的机制至关重要。在这项观察性队列研究中，我们收集了 34 名连续患有 irAE-n 的癌症患者（急性病期间）和 49 名癌症控制患者的血清和外周血样本无 irAE-n（ICI 治疗前和治疗中，n = 44 例，无高级别 irAE，n = 5 例，有高级别非神经系统 irAE）。患者接受抗程序性细胞死亡蛋白 (PD)-1 或抗 PD 配体 1 单一疗法或抗 PD-1/抗细胞毒性 T 淋巴细胞相关蛋白 4 联合疗法。最常见的癌症是黑色素瘤、肺癌和肝细胞癌。使用 48 标记单细胞质谱流式细胞术和多重细胞因子测定进行外周血免疫分析。在急性疾病期间，irAE-n 患者表现出较高频率的 CD8 效应记忆类型 (EM-)1 和中枢记忆 (CM) T细胞与没有 irAE 的对照细胞相比。多器官免疫毒性（神经性非神经性）与较高的 CD8 EM1 T 细胞计数相关。虽然整个队列中没有 B 细胞变化，但我们检测到自身抗体阳性 irAE-n 患者亚组中 IgD-CD11c CD21low 和 IgD-CD24 CD21high B 细胞显着减少。我们进一步确定了 irAE-n 患者趋化性和炎症增强的特征，并发现 CXCL10 作为诊断高级别免疫毒性（如 irAE-n）的有前景的标记物。我们证明 irAE-n 患者存在深刻且部分亚组特异性的免疫细胞失调，这可能会指导未来生物标志物的开发和靶向治疗方法。© 作者 2023。由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需权限，请发送电子邮件至：journals.permissions@oup.com。

Neurologic immune-related adverse events (irAE-n) are rare but severe toxicities of immune checkpoint inhibitor (ICI) treatment. To overcome diagnostic and therapeutic challenges, a better mechanistic understanding of irAE-n is paramount.In this observational cohort study, we collected serum and peripheral blood samples from 34 consecutive cancer patients with irAE-n (during acute illness) and 49 cancer control patients without irAE-n (pre- and on-ICI treatment, n = 44 without high-grade irAEs, n = 5 with high-grade nonneurologic irAEs). Patients received either anti-programmed cell death protein (PD)-1 or anti-PD ligand-1 monotherapy or anti-PD-1/anti-cytotoxic T-lymphocyte associated protein-4 combination therapy. Most common cancers were melanoma, lung cancer, and hepatocellular carcinoma. Peripheral blood immune profiling was performed using 48-marker single-cell mass cytometry and a multiplex cytokine assay.During acute illness, patients with irAE-n presented higher frequencies of CD8+ effector memory type (EM-)1 and central memory (CM) T cells compared to controls without irAEs. Multi-organ immunotoxicities (neurologic + nonneurologic) were associated with higher CD8+ EM1 T cell counts. While there were no B cell changes in the overall cohort, we detected a marked decrease of IgD- CD11c+ CD21low and IgD- CD24+ CD21high B cells in a subgroup of patients with autoantibody-positive irAE-n. We further identified signatures indicative of enhanced chemotaxis and inflammation in irAE-n patients and discovered CXCL10 as a promising marker to diagnose high-grade immunotoxicities such as irAE-n.We demonstrate profound and partly subgroup-specific immune cell dysregulation in irAE-n patients, which may guide future biomarker development and targeted treatment approaches.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.