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

Article11 July 2022 Transparent process USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII Feng Xie Feng Xie Institutes of Biology and Medical Science, Soochow University, Suzhou, China Contribution: Conceptualization, Data curation, Software, Formal analysis, ​Investigation, Writing - original draft, Project administration Search for more papers by this author Xiaoxue Zhou Xiaoxue Zhou MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Data curation, Software, Formal analysis, Methodology, Writing - review & editing Search for more papers by this author Heyu Li Heyu Li MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Data curation, Methodology Search for more papers by this author Peng Su Peng Su MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Methodology Search for more papers by this author Sijia Liu Sijia Liu orcid.org/0000-0002-1326-4932 Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands Contribution: Formal analysis, Methodology Search for more papers by this author Ran Li Ran Li The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China Contribution: Software, Formal analysis Search for more papers by this author Jing Zou Jing Zou MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Formal analysis Search for more papers by this author Xiang Wei Xiang Wei MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: ​Investigation Search for more papers by this author Chen Pan Chen Pan MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Software, Formal analysis Search for more papers by this author Zhengkui Zhang Zhengkui Zhang Institutes of Biology and Medical Science, Soochow University, Suzhou, China Contribution: Formal analysis, Methodology Search for more papers by this author Min Zheng Min Zheng 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 Contribution: Resources Search for more papers by this author Zhuang Liu Zhuang Liu Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, China Contribution: ​Investigation Search for more papers by this author Xuli Meng Xuli Meng Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China Contribution: Resources Search for more papers by this author Huib Ovaa Huib Ovaa Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands Contribution: Conceptualization Search for more papers by this author Peter ten Dijke Corresponding Author Peter ten Dijke [email protected] orcid.org/0000-0002-7234-342X Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands Contribution: ​Investigation Search for more papers by this author Fangfang Zhou Corresponding Author Fangfang Zhou [email protected] orcid.org/0000-0003-1870-7584 Institutes of Biology and Medical Science, Soochow University, Suzhou, China Contribution: Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Long Zhang Corresponding Author Long Zhang [email protected] orcid.org/0000-0001-8139-0474 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Feng Xie Feng Xie Institutes of Biology and Medical Science, Soochow University, Suzhou, China Contribution: Conceptualization, Data curation, Software, Formal analysis, ​Investigation, Writing - original draft, Project administration Search for more papers by this author Xiaoxue Zhou Xiaoxue Zhou MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Data curation, Software, Formal analysis, Methodology, Writing - review & editing Search for more papers by this author Heyu Li Heyu Li MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Data curation, Methodology Search for more papers by this author Peng Su Peng Su MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Methodology Search for more papers by this author Sijia Liu Sijia Liu orcid.org/0000-0002-1326-4932 Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands Contribution: Formal analysis, Methodology Search for more papers by this author Ran Li Ran Li The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China Contribution: Software, Formal analysis Search for more papers by this author Jing Zou Jing Zou MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Formal analysis Search for more papers by this author Xiang Wei Xiang Wei MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: ​Investigation Search for more papers by this author Chen Pan Chen Pan MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Software, Formal analysis Search for more papers by this author Zhengkui Zhang Zhengkui Zhang Institutes of Biology and Medical Science, Soochow University, Suzhou, China Contribution: Formal analysis, Methodology Search for more papers by this author Min Zheng Min Zheng 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 Contribution: Resources Search for more papers by this author Zhuang Liu Zhuang Liu Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, China Contribution: ​Investigation Search for more papers by this author Xuli Meng Xuli Meng Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China Contribution: Resources Search for more papers by this author Huib Ovaa Huib Ovaa Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands Contribution: Conceptualization Search for more papers by this author Peter ten Dijke Corresponding Author Peter ten Dijke [email protected] orcid.org/0000-0002-7234-342X Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands Contribution: ​Investigation Search for more papers by this author Fangfang Zhou Corresponding Author Fangfang Zhou [email protected] orcid.org/0000-0003-1870-7584 Institutes of Biology and Medical Science, Soochow University, Suzhou, China Contribution: Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Long Zhang Corresponding Author Long Zhang [email protected] orcid.org/0000-0001-8139-0474 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Author Information Feng Xie1,‡, Xiaoxue Zhou2,‡, Heyu Li2, Peng Su2, Sijia Liu3, Ran Li4, Jing Zou2, Xiang Wei2, Chen Pan2, Zhengkui Zhang1, Min Zheng5, Zhuang Liu6, Xuli Meng7, Huib Ovaa3,‡, Peter Dijke *,3, Fangfang Zhou *,1 and Long Zhang *,2 1Institutes of Biology and Medical Science, Soochow University, Suzhou, China 2MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China 3Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands 4The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China 5State 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 6Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, China 7Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China ‡ These authors contributed equally to this work *Corresponding author. Tel: +31 71 526 9200; E-mail: [email protected]**Corresponding author. Tel: +86 512 6588 2135; E-mail: [email protected]***Corresponding author. Tel: +86 571 8820 8375; E-mail: [email protected] The EMBO Journal (2022)41:e108791https://doi.org/10.15252/embj.2021108791 Deceased: Huib Ovaa Full textView the full text of the articlePDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info 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. Synopsis TGF-β signaling is a key factor in tumor progression and is associated with poor response to cancer immunotherapy. This work shows that pharmacologically targeting the deubiquitinase USP8 can antagonise TGF-β/SMAD signalling and improve the efficacy of cancer immunotherapy USP8 is a metastasis enhancer that directly deubiquitinates and stabilises TGF-β receptor TβRII, thereby promoting TGF-β/SMAD signaling. Gain of USP8 function promotes the secretion of TβRII+ circulating extracellular vesicles that induce CD8+ T cell exhaustion. Pharmacological inhibition of USP8 represses TGF-β signalling and inhibits cancer progression. USP8 inhibition alleviates CD8+ T cell exhaustion and improves the efficacy of breast cancer immunotherapy. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 41,Issue 16,16 August 2022This cover highlights the article Cryo‐EM reveals mechanisms of angiotensin I‐converting enzyme allostery and dimerization by Lizelle Lubbe, Edward D. Sturrock and colleagues. Angiotensin I‐converting enzyme (ACE) is crucial for blood pressure regulation. Here, we reveal the first structures of monomeric and dimeric ACE using cryo‐EM, and uncover mechanistic insights which light the way for the development of novel drugs to treat cardiovascular disease. This image illustrates how dimerization increases domain motions (cyan), activates a newly identified allosteric switch (yellow loop), and triggers key active site changes (yellow glow). The background shows 2D views of ACE, reminiscent of a cryo‐EM micrograph.(Scientific image by Lizelle Lubbe) Volume 41Issue 1616 August 2022In this issue ReferencesRelatedDetailsLoading ...