2. Academic Validation
  3. USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII

USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII

  • EMBO J. 2022 Aug 16;41(16):e108791. doi: 10.15252/embj.2021108791.
Feng Xie  # 1,  Xiaoxue Zhou  # 2,  Heyu Li 2,  Peng Su 2,  Sijia Liu 3,  Ran Li 4,  Jing Zou 2,  Xiang Wei 2,  Chen Pan 2,  Zhengkui Zhang 1,  Min Zheng 5,  Zhuang Liu 6,  Xuli Meng 7,  Huib Ovaa  # 3,  Peter Ten Dijke 3,  Fangfang Zhou 1,  Long Zhang 2
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 Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
  • 4 The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
  • 5 State Key Laboratory for Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou, China.
  • 6 Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, China.
  • 7 Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
  • # Contributed equally.
PMID: 35811497 DOI: 10.15252/embj.2021108791
Abstract

TGF-β signaling is a key player in tumor progression and immune evasion, and is associated with poor response to Cancer immunotherapies. Here, we identified ubiquitin-specific peptidase 8 (USP8) as a metastasis enhancer and a highly active Deubiquitinase in aggressive breast tumors. USP8 acts both as a Cancer stemness-promoting factor and an activator of the TGF-β/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF-β Receptor TβRII, leading to its increased expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-β/SMAD-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TβRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF-β/SMAD signaling, and reduces TβRII stability and the number of TβRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti-tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the Cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of Cancer Immunotherapy.

Keywords

TβRII; USP8; cancer immunotherapy; deubiquitinase; metastasis.

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