2. Academic Validation
  3. Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling

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

  • Nat Commun. 2022 Aug 1;13(1):4461. doi: 10.1038/s41467-022-31250-2.
Feng Xie  # 1,  Xiaoxue Zhou  # 2,  Peng Su 2,  Heyu Li 2,  Yifei Tu 2,  Jinjin Du 2,  Chen Pan 2,  Xiang Wei 2,  Min Zheng 3,  Ke Jin 4,  Liyan Miao 5,  Chao Wang 6,  Xuli Meng 7,  Hans van Dam 8,  Peter Ten Dijke 8,  Long Zhang 9,  Fangfang Zhou 10
Affiliations

Affiliations

  • 1 Institutes of Biology and Medical Science, Soochow University, Suzhou, China.
  • 2 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 3 State Key Laboratory for Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Hangzhou, China.
  • 4 Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, China.
  • 5 The first affiliated hospital of soochow university, Suzhou, China.
  • 6 Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, China.
  • 7 Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
  • 8 Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
  • 9 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. l_zhang@zju.edu.cn.
  • 10 Institutes of Biology and Medical Science, Soochow University, Suzhou, China. zhoufangfang@suda.edu.cn.
  • # Contributed equally.
PMID: 35915084 DOI: 10.1038/s41467-022-31250-2
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.

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