DNA methylation mediates the immunosuppressive tumour microenvironment in metastatic endometrial clear cell carcinoma.

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Huiqing Jia, Yang Chen, Guofeng Ma, Sicong Xu, Xiangyan Zhang, Lianpeng Chang, Ping Yang, Yujing Xiao, Xuefeng Xia, Shukun Zhang, Huaxiao Tang, Yilin Mou, Lina Zhang, Haoyan Wang, Jing Bai, Xin Yi, Xiaoming Xing
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引用次数: 0

Abstract

Background: Endometrial clear cell carcinoma (ECCC) is a rare and highly aggressive histological subtype of endometrial cancer with marked metastatic potential. The molecular characteristics and underlying mechanisms governing its metastatic behaviour remain poorly understood. This study aimed to delineate molecular distinctions between metastatic (Pm) and non-metastatic (Pn) primary ECCC tumours, elucidate DNA methylation-mediated regulatory mechanisms driving metastasis, and identify potential epigenetic biomarkers and therapeutic targets.

Methods: This multicentre study involved 51 individuals diagnosed with ECCC, leading to the establishment of two independent cohorts: a sequencing cohort (n = 35) for integrated whole-genome methylation and transcriptomic analysis, and a tissue microarray (TMA) cohort (n = 16) to validate key findings.

Findings: Tumours exhibiting metastasis were found to possess a profoundly immunosuppressive tumour microenvironment (TME), evidenced by reduced density of tumour-infiltrating lymphocytes (TILs), especially within subsets of anti-tumour immune cells. Further analysis highlighted differential hypermethylation events in Pm tumours that acted as crucial epigenetic switches regulating immune responses. Specifically, methylation at ETS1-binding sites influenced ETS1 regulon activity, thus broadly regulating immune response processes. Epigenetic silencing of key genes in the T cell receptor (TCR) signalling pathway, such as LCK, CD3E, and ZAP70, impaired T cell activation and inhibited the activity of interacting immune pathways. Additionally, we developed a Lasso-derived metastatic risk score model, incorporating TME features (TIL density) and epigenetic predictors (LCK methylation), which demonstrated strong predictive performance (area under the curve [AUC] = 0.859).

Interpretation: This study illuminated the "epigenetic-immune axis" as a central regulatory mechanism driving ECCC metastasis. DNA methylation systematically silenced immune response genes by targeting ETS1-binding sites and TCR signalling components, thus reconstructing the immunosuppressive TME to facilitate metastasis. The development of the metastatic risk score model and identification of LCK as a potential therapeutic target provide valuable strategies for precision treatment decisions and advancing targeted epigenetic-immune therapies in ECCC.

Funding: This work was supported by the National Natural Science Foundation of China, Joint Foundation Programme, Qingdao Municipal Science and Technology Bureau Municipal Science, Shenzhen Science and Technology Programme, and the Affiliated Hospital of Qingdao University Young Investigator Fund.

DNA甲基化介导转移性子宫内膜透明细胞癌的免疫抑制肿瘤微环境。
背景:子宫内膜透明细胞癌(ECCC)是一种罕见且高度侵袭性的子宫内膜癌组织学亚型,具有明显的转移潜力。控制其转移行为的分子特征和潜在机制仍然知之甚少。本研究旨在描述转移性(Pm)和非转移性(Pn)原发性ECCC肿瘤之间的分子差异,阐明DNA甲基化介导的驱动转移的调控机制,并确定潜在的表观遗传生物标志物和治疗靶点。方法:这项多中心研究纳入了51名诊断为ECCC的个体,建立了两个独立的队列:一个测序队列(n = 35)用于整合全基因组甲基化和转录组分析,另一个组织微阵列(TMA)队列(n = 16)用于验证关键发现。研究发现:表现出转移的肿瘤具有深刻的免疫抑制肿瘤微环境(TME),其证据是肿瘤浸润淋巴细胞(til)密度降低,特别是在抗肿瘤免疫细胞亚群中。进一步的分析强调了Pm肿瘤中不同的高甲基化事件,这些事件作为调节免疫反应的关键表观遗传开关。具体来说,ETS1结合位点的甲基化影响了ETS1调控活性,从而广泛调节免疫反应过程。T细胞受体(TCR)信号通路中的关键基因,如LCK、CD3E和ZAP70的表观遗传沉默,会损害T细胞的激活并抑制相互作用的免疫通路的活性。此外,我们开发了lasso衍生的转移风险评分模型,结合TME特征(TIL密度)和表观遗传预测因子(LCK甲基化),该模型显示出很强的预测性能(曲线下面积[AUC] = 0.859)。解释:本研究阐明了“表观遗传-免疫轴”作为驱动ECCC转移的中心调控机制。DNA甲基化通过靶向ets1结合位点和TCR信号组分,系统地沉默免疫应答基因,从而重建免疫抑制的TME,促进转移。转移风险评分模型的发展和LCK作为潜在治疗靶点的识别为ECCC的精确治疗决策和推进靶向表观遗传免疫治疗提供了有价值的策略。基金资助:国家自然科学基金、联合基金项目、青岛市科技局市科技局深圳市科技计划、青岛大学附属医院青年科研工作者基金资助。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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