Tumor necrosis factor receptor 2 promotes endothelial cell-mediated suppression of CD8+ T cells through tuning glycolysis in chemoresistance of breast cancer

作者：Yu Hu, Xiaohan Lou, Kaili Zhang, Longze Pan, Yueyue Bai, Linlin Wang, Ming Wang, Yan Yan, Jiajia Wan, Xiaohan Yao, Xixi Duan, Ni Chen, Zhihai Qin · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05472-5 · 被引用次数：10 · 研究领域：Angiogenesis and VEGF in Cancer、Single-cell and spatial transcriptomics、Immune cells in cancer

BACKGROUND: T cells play a pivotal role in chemotherapy-triggered anti-tumor effects. Emerging evidence underscores the link between impaired anti-tumor immune responses and resistance to paclitaxel therapy in triple-negative breast cancer (TNBC). Tumor-related endothelial cells (ECs) have potential immunoregulatory activity. However, how ECs regulate T cell activity during TNBC chemotherapy remains poorly understood. METHODS: Single-cell analysis of ECs in patients with TNBC receiving paclitaxel therapy was performed using an accessible single-cell RNA sequencing (scRNA-seq) dataset to identify key EC subtypes and their immune characteristics. An integrated analysis of a tumor-bearing mouse model, immunofluorescence, and a spatial transcriptome dataset revealed the spatial relationship between ECs, especially Tumor necrosis factor receptor (TNFR) 2+ ECs, and CD8+ T cells. RNA sequencing, CD8+ T cell proliferation assays, flow cytometry, and bioinformatic analyses were performed to explore the immunosuppressive function of TNFR2 in ECs. The downstream metabolic mechanism of TNFR2 was further investigated using RNA sequencing, cellular glycolysis assays, and western blotting. RESULTS: In this study, we identified an immunoregulatory EC subtype, characterized by enhanced TNFR2 expression in non-responders. By a mouse model of TNBC, we revealed a dynamic reduction in the proportion of the CD8+ T cell-contacting tumor vessels that could co-localize spatially with CD8+ T cells dur...