A bioorthogonal system reveals antitumour immune function of pyroptosis

doi:10.1038/s41586-020-2079-1

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2079-1
	A bioorthogonal system reveals antitumour immune function of pyroptosis
	Kim, Sungchul 1; Loeff, Luuk 1,5; Colombo, Sabina 1; Jergic, Slobodan 2,3,4; Brouns, Stan J. J.1; Joo, Chirlmin 1
	2020-02-08
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
文章类型	Article;Early Access
语种	英语
国家	Peoples R China
英文关键词	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-BF3) 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-BF3 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-BF3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3 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
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000519162500004
WOS关键词	DRUG ; PRINCIPLES ; ORGANOTRIFLUOROBORATE ; NANOPARTICLES ; CLEAVAGE ; DESIGN
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281504
专题	地球科学资源环境科学气候变化
作者单位	1.Delft Univ Technol, Kavli Inst Nanosci, Dept Bionanosci, Delft, Netherlands; 2.Univ Wollongong, Mol Horizons, Wollongong, NSW, Australia; 3.Univ Wollongong, Sch Chem & Mol Biosci, Wollongong, NSW, Australia; 4.Illawarra Hlth & Med Res Inst, Wollongong, NSW, Australia; 5.Univ Zurich, Dept Biochem, Zurich, Switzerland
推荐引用方式 GB/T 7714	Kim, Sungchul,Loeff, Luuk,Colombo, Sabina,et al. A bioorthogonal system reveals antitumour immune function of pyroptosis[J]. NATURE,2020.
APA	Kim, Sungchul,Loeff, Luuk,Colombo, Sabina,Jergic, Slobodan,Brouns, Stan J. J.,&Joo, Chirlmin.(2020).A bioorthogonal system reveals antitumour immune function of pyroptosis.NATURE.
MLA	Kim, Sungchul,et al."A bioorthogonal system reveals antitumour immune function of pyroptosis".NATURE (2020).