Cancer immunology data engine reveals secreted AOAH as a potential immunotherapy

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-07-28 DOI:10.1016/j.cell.2025.07.004

Lanqi Gong, Jie Luo, Emily Yang, Beibei Ru, Ziyang Qi, Yuma Yang, Anshu Rani, Abhilasha Purohit, Yu Zhang, Grace Guan, Rohit Paul, Trang Vu, Zuojia Chen, Renyue Ji, Chi-Ping Day, Chuan Wu, Glenn Merlino, David Fitzgerald, Grégoire Altan-Bonnet, Kenneth Aldape, Peng Jiang

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Abstract

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.

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癌症免疫学数据引擎显示分泌的AOAH是一种潜在的免疫疗法

分泌蛋白是细胞间通讯的中枢介质，可作为多种疾病的治疗靶点。编码分泌蛋白的人类基因约有1903个，很难通过普通的遗传方法进行研究。为了解决这一障碍，更广泛地说，为了发现癌症治疗方法，我们开发了癌症免疫学数据引擎（CIDE, https://cide.ccr.cancer.gov），它包含了90个组学数据集，涵盖了来自17种实体肿瘤类型的8,575个肿瘤特征和免疫治疗结果。CIDE系统地识别与免疫治疗结果相关的所有基因。然后，我们重点研究了CIDE中没有已知癌症作用的优先分泌蛋白，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。最受欢迎的乙酰氧酰基水解酶（AOAH）通过使T细胞受体对弱抗原敏感，并通过消耗免疫抑制剂花生四烯酰基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的免疫治疗。

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

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.