综合多素学揭示腺苷信号传导预测免疫疗法反应并调节黑色素瘤的肿瘤生态系统
Integrated multiomics revealed adenosine signaling predict immunotherapy response and regulate tumor ecosystem of melanoma
影响因子:4.30000
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
摘要
细胞外腺苷广泛参与调节肿瘤微环境。鉴于以腺苷为目标的治疗试验令人失望，可能需要个性化治疗，该治疗是针对个别患者的微环境状况量身定制的。在这里，我们使用非阴性基质分数介绍了腺苷信号得分（ADO-SCORE）模型，使用公开可用的黑色素瘤数据集鉴定出患者亚型，该数据集旨在介绍腺苷信号传导相关基因并构建一个预测预后的模型。我们分析了580种恶性黑色素瘤样品，并证明了其预后的强大价值。免疫检查点抑制剂数据集的进一步研究表明，其潜力是免疫检查点抑制剂功效的分层因素。我们验证了Xiangya医院黑色素瘤队列中蛋白质水平免疫荧光的ADO分数的能力。更重要的是，单细胞和空间转录组数据突出了腺苷信号传导相关基因的细胞特异性表达模式，以及黑色素瘤中肿瘤细胞和免疫细胞之间腺苷信号传导介导的串扰的存在。我们的研究揭示了黑色素瘤患者的腺苷信号传导与临床益处之间的牢固联系，并提出了一种普遍适用的腺苷信号传导模型，ADO分数，在基因表达谱和组织学切片中。该模型使我们能够更精确，方便地选择可能从免疫疗法中受益的患者。
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.