文章：

免疫相关皮肤不良事件根据靶向免疫检查点的不同，展现出独特的临床与分子特征。

Immune-Related Cutaneous Adverse Events Display Distinct Clinical and Molecular Characteristics, Depending on Immune Checkpoints Targeted

原文发布日期：14 June 2025

DOI: 10.3390/cancers17121992

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Immune-related cutaneous adverse events (ircAEs) are common complications of cancer immunotherapy and provide insight into immune-related adverse events (irAEs) more broadly. To enhance our molecular understanding, we characterized ircAEs resulting from single-agent (PD1) and combined immunotherapy regimens (P+C). Clinically, maculopapular rash (MPR) and toxic epidermal necrolysis (TEN) resemble ircAEs, providing a valuable basis for investigations.Methods: To investigate the transcriptome and immune infiltrates in ircAEs, we conducted transcriptomic analyses and multiplexed immunohistochemistry on skin biopsies from patients receiving PD1 and P+C, as well as those with MPR, TEN, and healthy controls.Results: Principal component analysis revealed distinct transcriptomic clustering between ircAEs, MPR, and TEN. Specifically, PD1 ircAEs exhibited a gene expression profile similar to TEN, with upregulation of Type-I-response-related genes (e.g., CXCL9 Log2FC 5.34,p< 0.0001, CXCL10 Log2FC 6.03,p< 0.0001), while P+C ircAEs more closely resembled MPR. Immune infiltrates differed significantly between all groups (p= 0.002 by PERMANOVA for all groups). CD4 T-cells were abundant in the dermis of ircAEs from any type of immunotherapy. However, PD1 stained positive in 1.07% of CD4 cells with PD1 monotherapy, compared to 0.3%, 0.4%, and 0.08% in P+C, MPR, and TEN, respectively.Conclusions: This study identified distinct molecular and cellular signatures in ircAEs depending on the type of immune checkpoint blockade. aPD1-associated ircAEs share similarities with the cytotoxic profile of TEN, while P+C more closely mirrored MPR. These findings support the need for tailored management strategies for ircAEs, emphasizing personalized therapeutic approaches to minimize treatment interruptions while preserving the efficacy of cancer immunotherapy.

摘要翻译： 

背景/目的：免疫相关皮肤不良事件是癌症免疫治疗的常见并发症，为更广泛理解免疫相关不良事件提供了重要窗口。为深化分子机制认知，本研究对单药（PD1抑制剂）与联合免疫方案（P+C）引发的免疫相关皮肤不良事件进行了特征分析。临床上，斑丘疹和中毒性表皮坏死松解症与免疫相关皮肤不良事件具有相似性，为研究提供了有价值的参照基础。 方法：通过转录组分析和多重免疫组化技术，对接受PD1单药、P+C联合治疗患者的皮肤活检样本，以及斑丘疹、中毒性表皮坏死松解症患者和健康对照者的样本进行检测，以探究免疫相关皮肤不良事件的转录组特征及免疫细胞浸润情况。 结果：主成分分析显示免疫相关皮肤不良事件、斑丘疹和中毒性表皮坏死松解症具有明显的转录组聚类差异。具体而言，PD1抑制剂相关皮肤不良事件呈现与中毒性表皮坏死松解症相似的基因表达谱，I型免疫反应相关基因显著上调；而P+C联合方案相关皮肤不良事件则更接近斑丘疹的分子特征。各组间免疫细胞浸润存在显著差异。各类免疫治疗引发的皮肤不良事件真皮层中均富含CD4 T细胞，但PD1单药治疗组中PD1阳性CD4细胞比例达1.07%，显著高于P+C联合组、斑丘疹组和中毒性表皮坏死松解症组。 结论：本研究发现免疫检查点抑制剂类型决定免疫相关皮肤不良事件具有独特的分子和细胞特征。PD1抑制剂相关皮肤不良事件与中毒性表皮坏死松解症的细胞毒性特征相似，而P+C联合方案则更接近斑丘疹模式。这些发现表明需要针对不同类型的免疫相关皮肤不良事件制定个体化管理策略，在维持癌症免疫治疗效果的同时最大限度减少治疗中断。

原文链接：

Immune-Related Cutaneous Adverse Events Display Distinct Clinical and Molecular Characteristics, Depending on Immune Checkpoints Targeted