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

Abstract

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).

Keywords: Bladder cancer; Myeloid cells; Prognosis; Single-cell RNA sequencing; Tumour microenvironment.