Sun Xiaopeng, Axelrod Margaret L, Gonzalez-Ericsson Paula I, Sanchez Violeta, Wang Yu, Curry Jonathan L, Phillips Elizabeth J, Xu Yaomin, Johnson Douglas B, Balko Justin M
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States.
Front Immunol. 2025 Mar 13;16:1542499. doi: 10.3389/fimmu.2025.1542499. eCollection 2025.
Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancy but can induce immune-related adverse events (irAE). The mechanisms behind these sporadic and sometimes life-threatening irAEs remain largely unexplored. Here, we present a case report and in-depth molecular analysis of an erythema nodosum (EN) like irAE occurring in a melanoma patient with isolated brain metastasis, aiming to explore the potential mechanism of this irAE.
We performed RNA and T cell receptor (TCR) sequencing on the patient's resected brain metastasis and biopsy of EN-like irAE. Single cell RNA/TCR sequencing was conducted on the patient's peripheral blood mononuclear cells (PBMC) at baseline, 3 weeks after ipilimumab and nivolumab combination therapy, during EN toxicity and after resolution.
The site of EN-like irAE showed a distinct accumulation of pro-inflammatory immune cells, accompanied by the upregulation of inflammatory and interferon response signatures. In addition, clonal expansion and activation of irAE-associated CD8 T cells and upregulation of monocyte-specific interferon signatures occurred concurrently with irAE onset.
The unique immune landscape at the EN-like irAE could indicate that this irAE is distinct from anti-tumor immune and analogous non-ICI autoimmune milieus. Our data also suggests that systemic immune activation induced by ICI treatment, as reflected in PBMC, may help monitor the patient's treatment response and access irAE risk.
免疫检查点抑制剂（ICI）越来越多地用于治疗晚期恶性肿瘤，但可诱发免疫相关不良事件（irAE）。这些偶发且有时危及生命的irAE背后的机制在很大程度上仍未得到探索。在此，我们报告一例黑色素瘤伴孤立性脑转移患者发生的类结节性红斑（EN）样irAE的病例，并进行深入的分子分析，旨在探究这种irAE的潜在机制。
我们对患者切除的脑转移瘤及类EN样irAE活检组织进行了RNA和T细胞受体（TCR）测序。在基线、伊匹单抗和纳武单抗联合治疗后3周、EN毒性发作期间及消退后，对患者外周血单个核细胞（PBMC）进行了单细胞RNA/TCR测序。
类EN样irAE部位显示促炎免疫细胞明显聚集，同时炎症和干扰素反应特征上调。此外，irAE相关CD8 T细胞的克隆扩增和激活以及单核细胞特异性干扰素特征的上调与irAE发作同时发生。
类EN样irAE独特的免疫格局可能表明这种irAE不同于抗肿瘤免疫和类似的非ICI自身免疫环境。我们的数据还表明，PBMC中反映的ICI治疗诱导的全身免疫激活可能有助于监测患者的治疗反应并评估irAE风险。
