High-resolution transcriptome atlas of bladder cancer highlights the functional myeloid subsets in modulating immune microenvironment

Background 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. Methods 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. 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. Interpretation 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. Funding 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).