ELN orchestrates prometastatic and immunosuppressive niche in bladder cancer via TGFB1 autocrine signaling
Wentao Xu, Jia Gao, Shanshan Wu, Jianshang Huang, Chenchen An, Chonggui Jiang, Nianping Liu, Chen Cheng, Zihan Wang, Zijian Dong, Yuchen Xu, Jun Zhou, Hanren Dai, Xiaolei Li, Honghai Xu, Songyun Zhao, Qianwen Fan, Yang Li, Ying Dai, Li Zuo, Hua Wang
Wentao Xu, Jia Gao, Shanshan Wu, Jianshang Huang, Chenchen An, Chonggui Jiang, Nianping Liu, Chen Cheng, Zihan Wang, Zijian Dong, Yuchen Xu, Jun Zhou, Hanren Dai, Xiaolei Li, Honghai Xu, Songyun Zhao, Qianwen Fan, Yang Li, Ying Dai, Li Zuo, Hua Wang
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Research Article Immunology Oncology

ELN orchestrates prometastatic and immunosuppressive niche in bladder cancer via TGFB1 autocrine signaling

Abstract

Bladder cancer (BCa) mortality is mainly driven by metastatic dissemination and an immunosuppressive tumor microenvironment. Here, we identify ELN (tropoelastin), an extracellular matrix protein abundantly secreted by cancer-associated fibroblasts (CAFs), as a critical determinant of these processes and a marker of poor prognosis. ELN promotes epithelial-mesenchymal transition (EMT), facilitates lymphatic spread, and induces immune dysfunction characterized by macrophage polarization toward an M2 phenotype and T cell exhaustion. Mechanistically, ELN functions as a binding partner of TGF-β receptor 2 (TGFBR2), thereby triggering SMAD2/3-dependent TGF-β1 secretion and establishing a feed forward signaling loop. This ELN/TGFBR2/TGF-β1 axis amplifies metastatic capacity and immunosuppressive signaling, ultimately accelerating disease progression and diminishing responsiveness to immune checkpoint blockade. Functional studies in BCa organoids and murine models demonstrated that pharmacologic blockade of the ELN-TGFBR2 interaction effectively suppressed tumor metastasis and restored antitumor immunity. Collectively, our findings establish ELN as a CAF-derived driver of metastasis and immune evasion in BCa. Targeting the ELN-TGFBR2 interaction offers a promising therapeutic strategy to limit metastatic progression and enhance the efficacy of immunotherapy in this lethal disease.

Authors

Wentao Xu, Jia Gao, Shanshan Wu, Jianshang Huang, Chenchen An, Chonggui Jiang, Nianping Liu, Chen Cheng, Zihan Wang, Zijian Dong, Yuchen Xu, Jun Zhou, Hanren Dai, Xiaolei Li, Honghai Xu, Songyun Zhao, Qianwen Fan, Yang Li, Ying Dai, Li Zuo, Hua Wang

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Figure 3

ELN+ CAFs shape an immunosuppressive microenvironment characterized by T cell exhaustion and M2 macrophage polarization.

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ELN+ CAFs shape an immunosuppressive microenvironment characterized by T...
(A) Scatter plots showing positive correlations between ELN expression and exhaustion scores, as well as M2 polarization scores in the TCGA-BLCA dataset. Spearman correlation was used. (B) Heatmap displaying the ORs of various cell types between ELN_high and ELN_low groups. (C) MacSpectrum analysis of monocytes and macrophages in ELN_high and ELN_low groups. (D) Violin plots comparing M1 and M2 scores between ELN_high and ELN_low groups. P values were determined by 2-tailed Mann-Whitney U test. (E) Representative flow-cytometric plots of PBMCs cocultured with PBS or rm-ELN. (F and G) Heatmaps showing the ORs of CD4+ T and CD8+ T cell subsets in PBS and rm-ELN groups. (H) Abundance of M2-like macrophage modules in PBS and rm-ELN groups. P value was determined by 2-tailed Mann-Whitney U test. (I) Cell-cell interaction analysis between CAFs and immune cell populations using CellPhoneDB. (J) Median importance of cell-type abundance in predicting the proximity of CAFs and immune cells within a spatial spot. (K and L) Representative flow-cytometric analysis of PD-1+ and LAG3+ T cells (K) or CD206+ macrophages (L) cocultured with NC or ELN-silenced CAFs. (M and N) Multiplex immunofluorescence staining of human BCa tissues showing spatial proximity of ELN+ CAF regions (ELN+Vimentin+, red/green) to immunosuppressive populations including Tregs (FOXP3+), PD-1+CD3+ T cells, and CD163+ macrophages. Red arrows highlight the specific colocalization. Scale bar: 100 µm. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.