Journal Article

A bioorthogonal system reveals antitumour immune function of pyroptosis

Zhou, Xuehan, Shao, Feng, Liu, Zhibo, Ding, Jingjin, Wang, Yupeng, Wang, Qinyang, Wang, Chunhong, Huang, Huanwei, Gao, Wenqing

2020

Overview

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 . 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 ) 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 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 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF 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.

• Publisher: Nature Publishing Group
• Subject: Animals / Antibodies / Apoptosis / Biological products / Cell death / 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 / 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 / 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 - immunology / Selectivity / Silanes - administration & dosage / Silanes - chemistry / Silanes - metabolism / Silanes - pharmacokinetics / Sodium / T cells / T-Lymphocytes - immunology / Transmission electron microscopy / Trastuzumab / Trastuzumab - administration & dosage / Trastuzumab - chemistry / Trastuzumab - metabolism / Trastuzumab - pharmacokinetics / Tumors / Viral antibodies / Xenograft Model Antitumor Assays