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

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.

• Authors: Feng Xie, Xiaoxue Zhou, Heyu Li, Peng Su, Sijia Liu, Ran Li, Jing Zou, Xiang Wei, Chen Pan, Zhengkui Zhang, Min Zheng, Zhuang Liu, Xuli Meng, Huib Ovaa, Peter Ten Dijke, Fangfang Zhou, Long Zhang
• Journal: The EMBO journal (EMBO J) Vol. 41 Issue 16 Pg. e108791 (08 16 2022) ISSN: 1460-2075 [Electronic] England
• PMID: 35811497 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors.

Chemical References

• Endosomal Sorting Complexes Required for Transport
• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II
• TGFBR2 protein, human
• Endopeptidases
• USP8 protein, human
• Ubiquitin Thiolesterase

Topics

• CD8-Positive T-Lymphocytes (metabolism)
• Endopeptidases (metabolism)
• Endosomal Sorting Complexes Required for Transport
• Extracellular Vesicles (metabolism)
• Humans
• Neoplasms (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics)
• Receptor, Transforming Growth Factor-beta Type II (genetics, metabolism)
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Signal Transduction
• Transforming Growth Factor beta (metabolism)
• Tumor Microenvironment
• Ubiquitin Thiolesterase (metabolism)