Gong Lanqi, Luo Jie, Yang Emily, Ru Beibei, Qi Ziyang, Yang Yuma, Rani Anshu, Purohit Abhilasha, Zhang Yu, Guan Grace, Paul Rohit, Vu Trang, Chen Zuojia, Ji Renyue, Day Chi-Ping, Wu Chuan, Merlino Glenn, Fitzgerald David, Altan-Bonnet Grégoire, Aldape Kenneth, Wu Jiansheng, Guan Xinyuan, Jiang Peng
Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China.
Cell. 2025 Sep 4;188(18):5062-5080.e32. doi: 10.1016/j.cell.2025.07.004. Epub 2025 Jul 28.
Secreted proteins are central mediators of intercellular communications and can serve as therapeutic targets in diverse diseases. The ∼1,903 human genes encoding secreted proteins are difficult to study through common genetic approaches. To address this hurdle and, more generally, to discover cancer therapeutics, we developed the Cancer Immunology Data Engine (CIDE, https://cide.ccr.cancer.gov), which incorporates 90 omics datasets spanning 8,575 tumor profiles with immunotherapy outcomes from 17 solid tumor types. CIDE systematically identifies all genes associated with immunotherapy outcomes. Then, we focused on secreted proteins prioritized by CIDE without known cancer roles and validated regulatory effects on immune checkpoint blockade for AOAH, CR1L, COLQ, and ADAMTS7 in mouse models. The top hit, acyloxyacyl hydrolase (AOAH), potentiates immunotherapies in multiple tumor models by sensitizing T cell receptors to weak antigens and protecting dendritic cells through depleting immunosuppressive arachidonoyl phosphatidylcholines and oxidized derivatives.
分泌蛋白是细胞间通讯的核心介质，可作为多种疾病的治疗靶点。约1903个编码分泌蛋白的人类基因难以通过常规遗传方法进行研究。为克服这一障碍，更广泛地发现癌症治疗方法，我们开发了癌症免疫数据引擎（CIDE，https://cide.ccr.cancer.gov），该引擎整合了90个组学数据集，涵盖8575个肿瘤图谱以及17种实体瘤类型的免疫治疗结果。CIDE系统地识别出所有与免疫治疗结果相关的基因。然后，我们聚焦于CIDE优先排序的、尚无已知癌症作用的分泌蛋白，并在小鼠模型中验证了AOAH、CR1L、COLQ和ADAMTS7对免疫检查点阻断的调节作用。排名第一的酰氧基酰基水解酶（AOAH）通过使T细胞受体对弱抗原敏感，并通过消耗免疫抑制性花生四烯酰磷脂酰胆碱和氧化衍生物来保护树突状细胞，从而增强多种肿瘤模型中的免疫治疗效果。
