Vogrig Alberto, Dentoni Marta, Florean Irene, Cellante Giulia, Domenis Rossana, Iacono Donatella, Pelizzari Giacomo, Rossi Simone, Damato Valentina, Fabris Martina, Valente Mariarosaria
Department of Medicine (DMED), University of Udine, Udine, Italy.
Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy.
Front Immunol. 2025 Mar 13;16:1548897. doi: 10.3389/fimmu.2025.1548897. eCollection 2025.
Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized oncology, significantly improving survival across multiple cancer types. ICIs, such as anti-PD-1 (e.g. nivolumab, pembrolizumab), anti-PD-L1 (e.g. atezolizumab, avelumab), and anti-CTLA-4 (e.g. ipilimumab), enhance T cell-mediated anti-tumor responses but can also trigger immune-related adverse events (irAEs). Neurological irAEs (n-irAEs), affecting 1-3% of patients, predominantly involve the peripheral nervous system; less commonly, n-irAEs can present as central nervous system disorders. Although irAEs suggest a possible correlation with treatment efficacy, their mechanisms remain unclear, with hypotheses ranging from antigen mimicry to cytokine dysregulation and microbiome alterations. Identifying patients at risk for n-irAEs and predicting their outcome through biomarkers would be highly desirable. For example, patients with high-risk onconeural antibodies (such as anti-Hu or Ma2), and elevated neurofilament light chain (NfL) levels often respond poorly to irAE treatment. However, interpreting neuronal antibody tests in the diagnosis of n-irAEs requires caution: positive results must align with the clinical context, as some cancer patients (e.g., SCLC) may have asymptomatic low antibody levels, and false positive results are common without tissue-based confirmation. Also, the use of biomarkers (e.g. IL-6) may lead to more targeted treatments of irAEs, minimizing adverse effects without compromising the anti-tumor efficacy of ICIs. This review provides a comprehensive overview of the latest findings on n-irAEs associated with ICIs, with a focus on their prediction, prevention, as well as precision treatment using autoantibodies, cytokines, and microbiota. The most interesting data concern neuronal antibodies, which we explore in their pathogenic roles and as biomarkers of neurotoxicity. Most of the available data on cytokines, both regarding their role as diagnostic and prognostic biomarkers and their role in supporting therapeutic decisions for toxicities, refer to non-neurological toxicities. However, in our review, we mention the potential role of CXCL10 and CXCL13 as biomarkers of n-irAEs and describe the current evidence, as well as the need for further studies, on the use of cytokines in guiding selection of second-line therapies for n-irAEs. Finally, no specific microbiome-related microbial signature has been proven to be linked to n-irAEs specifically, leading to the need of more future research on the topic.
使用免疫检查点抑制剂（ICI）的癌症免疫疗法彻底改变了肿瘤学，显著提高了多种癌症类型患者的生存率。ICI，如抗PD-1（如纳武单抗、帕博利珠单抗）、抗PD-L1（如阿特珠单抗、阿维鲁单抗）和抗CTLA-4（如伊匹木单抗），可增强T细胞介导的抗肿瘤反应，但也可能引发免疫相关不良事件（irAE）。神经学irAE（n-irAE）影响1%-3%的患者，主要累及外周神经系统；较少见的是，n-irAE可表现为中枢神经系统疾病。尽管irAE提示可能与治疗疗效相关，但其机制仍不清楚，假说范围从抗原模拟到细胞因子失调和微生物群改变。识别有n-irAE风险的患者并通过生物标志物预测其预后将非常有必要。例如，具有高风险肿瘤神经抗体（如抗Hu或Ma2）以及神经丝轻链（NfL）水平升高的患者对irAE治疗的反应通常较差。然而，在n-irAE诊断中解读神经元抗体检测需要谨慎：阳性结果必须与临床情况相符，因为一些癌症患者（如小细胞肺癌）可能有无症状的低抗体水平，并且在没有基于组织的确认时假阳性结果很常见。此外，使用生物标志物（如IL-6）可能导致对irAE进行更有针对性的治疗，在不影响ICI抗肿瘤疗效的情况下将不良反应降至最低。本综述全面概述了与ICI相关的n-irAE的最新发现，重点关注其预测、预防以及使用自身抗体、细胞因子和微生物群的精准治疗。最有趣的数据涉及神经元抗体，我们探讨了它们的致病作用以及作为神经毒性生物标志物的情况。关于细胞因子的大多数现有数据，无论是其作为诊断和预后生物标志物的作用，还是其在支持毒性治疗决策中的作用，都涉及非神经毒性。然而，在我们的综述中，我们提到了CXCL10和CXCL13作为n-irAE生物标志物的潜在作用，并描述了关于细胞因子在指导n-irAE二线治疗选择中的应用的现有证据以及进一步研究的必要性。最后，尚未证实有任何特定的与微生物群相关的微生物特征与n-irAE有特异性关联，因此需要对该主题进行更多的未来研究。
