Shi Zhiyuan, Sun Zhao, Zhang Dingding, Zhao Lin
Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China.
Center for Prevention and Early Intervention, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan,Wangfujing, Dongcheng District, Beijing, 100730, China.
Discov Oncol. 2025 Jul 1;16(1):1210. doi: 10.1007/s12672-025-02607-y.
The severe adverse events of immunotherapy have limited its clinical application. Immune cell characteristics and plasma metabolites are probably associated with immune-related adverse events, but current studies have not combined the three dynamically. This study is designed to analyze causality between immune cell characteristics and immune-related adverse events, and the degree to which plasma metabolites mediate it.
Data were obtained from genome-wide association studies. Initially, we conducted a two-sample bidirectional Mendelian randomization analysis to assess causal links between immune cell characteristics and immune-related adverse events. Following that, a two-step Mendelian randomization approach was utilized to measure the proportion of total effects mediated by 1400 plasma metabolites. Additionally, sensitivity analyses were conducted at each step to reduce horizontal pleiotropy and heterogeneity.
We identified 12 immune cell characteristics, and 31 plasma metabolites causally associated with immune-related adverse events. Through mediation effect analysis, 6 immune cell characteristics (CD4 on monocyte,CM CD4 + AC, EM CD4 + %T cell, CD39 + CD4 + AC, HLA DR on CD14 + CD16 + monocyte, CD45RA on TD CD8br) were identified as being correlated with the presence of immune-related adverse events, which were partially mediated by 5 metabolic characteristics (Ornithine to phosphate ratio, 1-palmitoyl-GPE (16:0) levels, 5-hydroxyhexanoate levels, (2,4 or 2,5)-dimethylphenol sulfate levels, 2-palmitoleoyl-GPC (16:1) levels). Among them, 2-palmitoleoyl-GPC (16:1) levels demonstrated the most significant mediating effect, mediating 10.8% (p = 0.0155) of the effect of CD45RA on TD CD8br on immune-related adverse events. The mediating effect is derived through a two-step MR analysis.
We identified genetic causality among the characteristics of immune cells, plasma metabolites, and immune-related adverse events. By regulating immune cells and plasma metabolites through various methods, it may be possible to alleviate immune-related adverse events. This discovery serves as a valuable reference for the judicious application of immunotherapy in future endeavors.
免疫疗法的严重不良事件限制了其临床应用。免疫细胞特征和血浆代谢物可能与免疫相关不良事件有关，但目前的研究尚未将三者动态结合起来。本研究旨在分析免疫细胞特征与免疫相关不良事件之间的因果关系，以及血浆代谢物介导这种关系的程度。
数据来自全基因组关联研究。最初，我们进行了两样本双向孟德尔随机化分析，以评估免疫细胞特征与免疫相关不良事件之间的因果联系。随后，采用两步孟德尔随机化方法来测量1400种血浆代谢物介导的总效应比例。此外，在每一步进行敏感性分析，以减少水平多效性和异质性。
我们确定了12种免疫细胞特征和31种与免疫相关不良事件有因果关系的血浆代谢物。通过中介效应分析，确定了6种免疫细胞特征（单核细胞上的CD4、中枢记忆CD4 +辅助性T细胞、效应记忆CD4 + T细胞百分比、CD39 + CD4 +辅助性T细胞、CD14 + CD16 +单核细胞上的HLA DR、终末分化CD8 +记忆T细胞上的CD45RA）与免疫相关不良事件的存在相关，这些事件部分由5种代谢特征（鸟氨酸与磷酸盐比值、1-棕榈酰甘油磷酸乙醇胺（16:0）水平、5-羟基己酸水平、（2,4或2,5）-二甲基苯酚硫酸盐水平、2-棕榈油酰甘油磷酸胆碱（16:1）水平）介导。其中，2-棕榈油酰甘油磷酸胆碱（16:1）水平显示出最显著的中介作用，介导了CD45RA对终末分化CD8 +记忆T细胞影响免疫相关不良事件的10.8%（p = 0.0155）。中介效应通过两步孟德尔随机化分析得出。
我们确定了免疫细胞特征、血浆代谢物和免疫相关不良事件之间的遗传因果关系。通过各种方法调节免疫细胞和血浆代谢物，可能减轻免疫相关不良事件。这一发现为未来免疫疗法的合理应用提供了有价值的参考。
