A bioorthogonal system reveals antitumour immune function of pyroptosis

Qinyang Wang, Yupeng Wang, Jingjin Ding, Chunhong Wang, Xuehan Zhou, Wenqing Gao, Huanwei Huang, Feng Shao () and Zhibo Liu ()
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Qinyang Wang: Peking University
Yupeng Wang: Chinese Academy of Medical Sciences
Jingjin Ding: National Institute of Biological Sciences
Chunhong Wang: Peking University
Xuehan Zhou: Peking University
Wenqing Gao: National Institute of Biological Sciences
Huanwei Huang: National Institute of Biological Sciences
Feng Shao: Chinese Academy of Medical Sciences
Zhibo Liu: Peking University

Nature, 2020, vol. 579, issue 7799, 421-426

Abstract: 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 pyroptosis1–5. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2079-1

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