A bioorthogonal system reveals antitumour immune function of pyroptosis

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis 1 – 5 . Pyroptosis i...

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Veröffentlicht in:Nature (London) 2020-03, Vol.579 (7799), p.421-426
Hauptverfasser: Wang, Qinyang, Wang, Yupeng, Ding, Jingjin, Wang, Chunhong, Zhou, Xuehan, Gao, Wenqing, Huang, Huanwei, Shao, Feng, Liu, Zhibo
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container_end_page 426
container_issue 7799
container_start_page 421
container_title Nature (London)
container_volume 579
creator Wang, Qinyang
Wang, Yupeng
Ding, Jingjin
Wang, Chunhong
Zhou, Xuehan
Gao, Wenqing
Huang, Huanwei
Shao, Feng
Liu, Zhibo
description Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis 1 – 5 . Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF 3 ) that can enter cells desilylates and ‘cleaves’ a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody–drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF 3 could release a client protein—including an active gasdermin—from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF 3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF 3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade. In mouse models of cancer, a biorthogonal chemical system based on desilylation catalysed by phenylalanine trifluoroborate enables the controlled release of gasdermin to induce pyroptosis selectively in tumour cells
doi_str_mv 10.1038/s41586-020-2079-1
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Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis 1 – 5 . Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF 3 ) that can enter cells desilylates and ‘cleaves’ a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody–drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF 3 could release a client protein—including an active gasdermin—from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF 3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF 3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade. 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The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF 3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF 3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade. 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Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Earth, Atmospheric &amp; Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Qinyang</au><au>Wang, Yupeng</au><au>Ding, Jingjin</au><au>Wang, Chunhong</au><au>Zhou, Xuehan</au><au>Gao, Wenqing</au><au>Huang, Huanwei</au><au>Shao, Feng</au><au>Liu, Zhibo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A bioorthogonal system reveals antitumour immune function of pyroptosis</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>579</volume><issue>7799</issue><spage>421</spage><epage>426</epage><pages>421-426</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis 1 – 5 . Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF 3 ) that can enter cells desilylates and ‘cleaves’ a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody–drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF 3 could release a client protein—including an active gasdermin—from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF 3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF 3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade. In mouse models of cancer, a biorthogonal chemical system based on desilylation catalysed by phenylalanine trifluoroborate enables the controlled release of gasdermin to induce pyroptosis selectively in tumour cells</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32188939</pmid><doi>10.1038/s41586-020-2079-1</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-9562-7791</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0028-0836
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1476-4687
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source MEDLINE; Nature; Alma/SFX Local Collection
subjects 59/78
631/250/1933
631/67/580
631/92
64/60
82/83
Animals
Antibodies
Apoptosis
Coumarins - administration & dosage
Coumarins - chemistry
Coumarins - metabolism
Coumarins - pharmacokinetics
Delayed-Action Preparations - administration & dosage
Delayed-Action Preparations - chemistry
Delayed-Action Preparations - metabolism
Delayed-Action Preparations - pharmacokinetics
Electron microscopy
Female
Fluorescence
Fluorides
Green Fluorescent Proteins - administration & dosage
Green Fluorescent Proteins - chemistry
Green Fluorescent Proteins - metabolism
Green Fluorescent Proteins - pharmacokinetics
HeLa Cells
Humanities and Social Sciences
Humans
Immune response
Immunoconjugates - administration & dosage
Immunoconjugates - chemistry
Immunoconjugates - metabolism
Immunoconjugates - pharmacokinetics
Inflammasomes - immunology
Inflammation - immunology
Inflammation - metabolism
Inflammation - pathology
Mammalian cells
Mammary Neoplasms, Experimental - immunology
Mammary Neoplasms, Experimental - metabolism
Mammary Neoplasms, Experimental - pathology
Mice
Mice, Inbred BALB C
Monoclonal antibodies
multidisciplinary
Mutation
Nanoparticles
Observations
Oligopeptides - administration & dosage
Oligopeptides - chemistry
Oligopeptides - metabolism
Oligopeptides - pharmacokinetics
Programmed Cell Death 1 Receptor - antagonists & inhibitors
Proteins
Proteins - administration & dosage
Proteins - chemistry
Proteins - metabolism
Proteins - pharmacokinetics
Pyroptosis
Pyroptosis - immunology
Science
Science (multidisciplinary)
Selectivity
Silanes - administration & dosage
Silanes - chemistry
Silanes - metabolism
Silanes - pharmacokinetics
Sodium
T-Lymphocytes - immunology
Transmission electron microscopy
Trastuzumab
Trastuzumab - administration & dosage
Trastuzumab - chemistry
Trastuzumab - metabolism
Trastuzumab - pharmacokinetics
Tumors
Xenograft Model Antitumor Assays
title A bioorthogonal system reveals antitumour immune function of pyroptosis
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