Tang Liansha, He Wenbo, Hu Handan, Liu Jiyan, Li Zhike
Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.
Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu 610041, China.
Biomedicines. 2025 Jul 14;13(7):1717. doi: 10.3390/biomedicines13071717.
Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet severe immune-related adverse events (irAEs) often necessitate immunotherapy discontinuation and cause life-threatening complications. Circulating plasma proteins, dynamically accessible and functionally linked to immunity, may predict and offer novel targets for irAEs. Leveraging multi-omics integration, we conducted bidirectional two-sample Mendelian randomization (MR) using protein quantitative trait loci (pQTLs) from 4998 plasma proteins and genome-wide association data of irAE phenotypes. A causal inference framework combining colocalization analysis, multivariable MR (MVMR) adjusting for body mass index (BMI) confounding, and mediation MR elucidated BMI-independent pathways. Systems biology approaches including tissue-specific expression profiling, pathway enrichment, and protein interaction network analysis revealed spatial and functional drivers of irAE pathogenesis. Proteome-wide MR mapping identified eight plasma proteins (CCL20, CSF1, CXCL9, CD40, TGFβ1, CLSTN2, TNFSF12, TGFα) causally associated with all-grade irAEs, and five (CCL20, CCL25, CXCL10, ADA, TGFα) with high-grade irAEs. Colocalization prioritized CD40/TNFSF12 (all-grade) and ADA/CCL25 (high-grade) as therapeutic targets (PPH4 > 0.7). CXCL9/TNFSF12 (all-grade) and CCL25 (high-grade) exerted BMI-independent effects, suggesting intrinsic immune dysregulation mechanisms. Tissue-specific gene expression patterns, CSF1, TGFβ1 in lung, TNFSF12 in the ileum may explain organ-specific irAE vulnerabilities. High-grade irAEs correlated with compartmentalized immune dysregulation and IL-17/immunodeficiency pathway activation. This study establishes the causal atlas of plasma proteins in irAE pathogenesis, bridging biomarker discovery with actionable therapeutic targets. These advances align with next-generation immunotherapy goals: maximizing efficacy while taming the immune storm.
免疫检查点抑制剂（ICIs）已经改变了癌症治疗方式，但严重的免疫相关不良事件（irAEs）常常需要停止免疫治疗，并会导致危及生命的并发症。循环血浆蛋白可动态获取且与免疫功能相关，可能预测irAEs并为其提供新的靶点。利用多组学整合技术，我们使用来自4998种血浆蛋白的蛋白质定量性状位点（pQTLs）和irAE表型的全基因组关联数据进行了双向两样本孟德尔随机化（MR）。一个结合共定位分析、针对体重指数（BMI）混杂因素进行调整的多变量MR（MVMR）以及中介MR的因果推断框架阐明了与BMI无关的途径。包括组织特异性表达谱分析、通路富集分析和蛋白质相互作用网络分析在内的系统生物学方法揭示了irAE发病机制的空间和功能驱动因素。全蛋白质组MR图谱确定了8种与所有级别的irAEs有因果关联的血浆蛋白（CCL20、CSF1、CXCL9、CD40、TGFβ1、CLSTN2、TNFSF12、TGFα），以及5种与高级别irAEs有因果关联的血浆蛋白（CCL20、CCL25、CXCL10、ADA、TGFα）。共定位分析将CD40/TNFSF12（所有级别）和ADA/CCL25（高级别）优先列为治疗靶点（后验概率>0.7）。CXCL9/TNFSF12（所有级别）和CCL25（高级别）发挥了与BMI无关的作用，提示存在内在免疫失调机制。组织特异性基因表达模式，如肺中的CSF1、TGFβ1，回肠中的TNFSF12，可能解释了器官特异性的irAE易感性。高级别irAEs与局部免疫失调和IL-17/免疫缺陷通路激活相关。本研究建立了irAE发病机制中血浆蛋白的因果图谱，将生物标志物发现与可操作的治疗靶点联系起来。这些进展与下一代免疫治疗目标一致：在控制免疫风暴的同时最大化疗效。
