Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling

Feng Xie, Xiaoxue Zhou, Peng Su, Heyu Li, Yifei Tu, Jinjin Du, Chen Pan, Xiang Wei, Min Zheng, Ke Jin, Liyan Miao, Chao Wang, Xuli Meng, Hans Dam, Peter Dijke, Long Zhang () and Fangfang Zhou ()
Additional contact information
Feng Xie: Soochow University
Xiaoxue Zhou: Zhejiang University
Peng Su: Zhejiang University
Heyu Li: Zhejiang University
Yifei Tu: Zhejiang University
Jinjin Du: Zhejiang University
Chen Pan: Zhejiang University
Xiang Wei: Zhejiang University
Min Zheng: Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease
Ke Jin: Sichuan University
Liyan Miao: The first affiliated hospital of soochow university
Chao Wang: Soochow University
Xuli Meng: Zhejiang Provincial People’s Hospital
Hans Dam: Leiden University Medical Center
Peter Dijke: Leiden University Medical Center
Long Zhang: Zhejiang University
Fangfang Zhou: Soochow University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Cancer immunotherapies have shown clinical success in various types of tumors but the patient response rate is low, particularly in breast cancer. Here we report that malignant breast cancer cells can transfer active TGF-β type II receptor (TβRII) via tumor-derived extracellular vesicles (TEV) and thereby stimulate TGF-β signaling in recipient cells. Up-take of extracellular vesicle-TβRII (EV-TβRII) in low-grade tumor cells initiates epithelial-to-mesenchymal transition (EMT), thus reinforcing cancer stemness and increasing metastasis in intracardial xenograft and orthotopic transplantation models. EV-TβRII delivered as cargo to CD8+ T cells induces the activation of SMAD3 which we demonstrated to associate and cooperate with TCF1 transcription factor to impose CD8+ T cell exhaustion, resulting in failure of immunotherapy. The levels of TβRII+ circulating extracellular vesicles (crEV) appears to correlate with tumor burden, metastasis and patient survival, thereby serve as a non-invasive screening tool to detect malignant breast tumor stages. Thus, our findings not only identify a possible mechanism by which breast cancer cells can promote T cell exhaustion and dampen host anti-tumor immunity, but may also identify a target for immune therapy against the most devastating breast tumors.

Date: 2022
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DOI: 10.1038/s41467-022-31250-2

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