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 8

Targeting the ELN/TGFBR2 axis improves the immunotherapeutic response in vivo.

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Targeting the ELN/TGFBR2 axis improves the immunotherapeutic response in...
(A) Schematic illustrating the MB49 orthotopic BCa model and the treatment schedule. Mice were treated with anti–PD-1 or IgG, combined with rm-ELN, ITD1, or αTGF-β as indicated. (B and C) Representative images of harvested orthotopic tumors (B) and endpoint tumor weights (C) in each treatment group. n = 7 for each group. P values were determined by 1-way ANOVA followed by Tukey’s multiple-comparison test. (D and E) Longitudinal bioluminescence imaging (D) and quantification of relative luminescence intensity (E) over 21 days. P values were determined by 2-way ANOVA with Tukey’s post hoc test. (F) Quantification of Ki67+ proliferating cells and cleaved-caspase 3+ apoptotic cells within orthotopic tumors across treatment groups. P values were determined by 1-way ANOVA followed by Tukey’s multiple-comparison test. (G) t-SNE visualization of spectral flow cytometry data displaying tumor-infiltrating immune cell subsets, including Tregs, exhausted T cells (PD-1+, LAG3+), and M2-like macrophages under the indicated treatments. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001.