整合多组学揭示腺苷信号通路预测免疫治疗反应及调控黑色素瘤肿瘤生态系统
Integrated multiomics revealed adenosine signaling predict immunotherapy response and regulate tumor ecosystem of melanoma
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影响因子:4.3
分区:医学2区 / 遗传学2区
发表日期:2024 Sep 15
作者:
Yantao Xu, Poyee Lau, Xiang Chen, Shuang Zhao, Yi He, Zixi Jiang, Xiang Chen, Guanxiong Zhang, Hong Liu
DOI:
10.1186/s40246-024-00651-3
摘要
细胞外腺苷在调控肿瘤微环境中发挥重要作用。鉴于腺苷靶向治疗试验的失望结果,个性化治疗可能成为必要,需根据个体患者的微环境状态进行定制。本研究引入腺苷信号通路评分(ADO-score)模型,利用公开的黑色素瘤数据集,通过非负矩阵分解方法识别患者亚型,旨在分析腺苷信号相关基因,并构建预测预后的模型。分析了580个黑色素瘤样本,验证了其在预后中的稳健价值。在免疫检查点抑制剂(ICI)数据集中进一步验证其作为免疫疗效分层指标的潜力。我们在湘雅医院的黑色素瘤队列中通过免疫荧光验证了ADO-score的蛋白水平表达能力。更重要的是,单细胞和空间转录组数据揭示了腺苷信号相关基因的细胞特异性表达模式,以及肿瘤细胞与免疫细胞之间基于腺苷信号的通讯。研究显示,腺苷信号与黑色素瘤患者的临床获益密切相关,提出了一个广泛适用的腺苷信号模型——ADO-score,可在基因表达谱和组织切片中应用,使得更精准、便捷地筛选出可能获益于免疫治疗的患者。
Abstract
Extracellular adenosine is extensively involved in regulating the tumor microenvironment. Given the disappointing results of adenosine-targeted therapy trials, personalized treatment might be necessary, tailored to the microenvironment status of individual patients. Here, we introduce the adenosine signaling score (ADO-score) model using non-negative matrix fraction identified patient subtypes using publicly available melanoma dataset, which aimed to profile adenosine signaling-related genes and construct a model to predict prognosis. We analyzed 580 malignant melanoma samples and demonstrated its robust value for prognosis. Further investigation in immune checkpoint inhibitor dataset suggests its potential as a stratified factor of immune checkpoint inhibitor efficacy. We validated the power of the ADO-score at the protein level immunofluorescence in a melanoma cohort from Xiangya Hospital. More importantly, single-cell and spatial transcriptomic data highlighted the cell-specific expression patterns of adenosine signaling-related genes and the existence of adenosine signaling-mediated crosstalk between tumor cells and immune cells in melanoma. Our study reveals a robust connection between adenosine signaling and clinical benefits in melanoma patients and proposes a universally applicable adenosine signaling model, the ADO-score, in gene expression profiles and histological sections. This model enables us to more precisely and conveniently select patients who are likely to benefit from immunotherapy.