CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8(+) T cells.
Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8(+) T cells.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
尽管对耗竭T细胞的染色质景观已有广泛研究，但人类TIL（肿瘤浸润淋巴细胞）（TILs）异质性功能状态和功能障碍状态背后的转录调控机制仍未完全阐明。
在此，我们利用单细胞染色质图谱技术，在涵盖四种癌症类型的广泛功能性和功能障碍性CD8+ TIL状态中鉴定了基因调控景观。
我们通过将单细胞染色质可及性与来自肿瘤类型匹配样本的单细胞RNA-seq数据整合，绘制了人类TILs中的增强子-启动子相互作用，并通过超级增强子分析优先筛选细胞状态特异性基因。除了揭示耗竭TILs中实体特异性的染色质重塑外，我们的分析还鉴定了一条通向TIL功能障碍的共同染色质轨迹，并确定了参与该过程的关键增强子、转录调控因子和失调基因。
最后，我们通过使用强效CRISPR激活子和抑制子靶向非编码调控元件，在免疫治疗相关位点验证了增强子调控。总之，我们的研究为理解和操控人类TIL（肿瘤浸润淋巴细胞）的细胞状态特异性基因调控线索提供了一个框架。
Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood.
Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8 + TIL states covering four cancer entities using single-cell chromatin profiling.
We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis. Besides revealing entity-specific chromatin remodeling in exhausted TILs, our analyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcriptional regulators, and deregulated genes involved in this process.
Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.
MEMBER ACCOUNT
登录成功会直接打开下一页。
