Liu Jiachen, Shi Zhen, Li Yajian, Ma Jie, Yao Jiaying, Yuan Zan, Wang Yuanhao, Yang Chunyuan, Li Xiao, Xing Nianzeng, Zhu Yunping, Zhang Jianhong, Wu Li
Institute for Immunology, Tsinghua-Peking Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China.
Department of Urology, State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Urologic Cancer Cell and Gene Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
EBioMedicine. 2025 Jul;117:105801. doi: 10.1016/j.ebiom.2025.105801. Epub 2025 Jun 24.
Despite the recent advancements in characterizing the heterogeneity of the tumour microenvironment (TME), the immunological understanding of myeloid subsets in bladder cancer (BC) remains restricted. A more comprehensive exploration of myeloid cells in BC may uncover critical immune-modulating features.
We employed density gradient centrifugation to enrich the population of immune cells and collected paired tumour and normal bladder tissues from 11 patients with bladder cancer for single-cell transcriptome analysis. Additionally, in vitro cultures and mouse tumour models were further used to validate our findings.
We revealed the metabolic alterations in TREM2 macrophages and CMA1 mast cells within BC tissues, and further demonstrated that knockout of Trem2 significantly reprogrammed the TME and upregulated PD-L1 expression on dendritic cells (DCs). Our deconvolution analysis elucidated the prognostic value of CMA1 mast cells, CD1C DCs and LAMP3 DCs in BC, as well as delineated four distinct immune cellular modules to investigate their cellular associations. Furthermore, our exploration of the interactome landscapes highlighted the anti-tumour effect of App knockdown in remodelling the TME, as well as the pivotal roles of ANNEXIN and GALECTIN pathways in BC pathogenesis.
Our findings provide a high-resolution resource for BC, elucidating the functional myeloid cell states, including TREM2 macrophages, CMA1 mast cells, and CD1C DCs. Furthermore, our study demonstrates that TREM2 and APP function as immune-modulating molecules, with potential therapeutic implications in the context of bladder cancer.
National Natural Science Foundation of China (31991174); the National Key Research and Development Program of China (2021YFA1301603 and 2023YFC2507000); the National Basic Science Center Program of China (82388101); the National Key Research and Development Program of China (2019YFA0508502 and 2022YFC2505001).
尽管近期在表征肿瘤微环境（TME）的异质性方面取得了进展，但对膀胱癌（BC）中髓系亚群的免疫学认识仍然有限。对BC中髓系细胞进行更全面的探索可能会揭示关键的免疫调节特征。
我们采用密度梯度离心法富集免疫细胞群体，并从11例膀胱癌患者中收集配对的肿瘤组织和正常膀胱组织进行单细胞转录组分析。此外，还进一步利用体外培养和小鼠肿瘤模型来验证我们的发现。
我们揭示了BC组织中TREM2巨噬细胞和CMA1肥大细胞的代谢改变，并进一步证明敲除Trem2可显著重塑TME并上调树突状细胞（DC）上的PD-L1表达。我们的反卷积分析阐明了CMA1肥大细胞、CD1C DC和LAMP3 DC在BC中的预后价值，并描绘了四个不同的免疫细胞模块以研究它们的细胞关联。此外，我们对相互作用组景观的探索突出了App敲低在重塑TME中的抗肿瘤作用，以及膜联蛋白和半乳糖凝集素途径在BC发病机制中的关键作用。
我们的研究结果为BC提供了一个高分辨率资源，阐明了功能性髓系细胞状态，包括TREM2巨噬细胞、CMA1肥大细胞和CD1C DC。此外，我们的研究表明TREM2和APP作为免疫调节分子发挥作用，在膀胱癌背景下具有潜在的治疗意义。
国家自然科学基金（31991174）；国家重点研发计划（2021YFA1301603和2023YFC2507000）；国家基础科学中心项目（82388101）；国家重点研发计划（2019YFA0508502和2022YFC2505001）。
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