A bioorthogonal system reveals antitumour immune function of pyroptosis
A bioorthogonal system reveals antitumour immune function of pyroptosis
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生物正交系统揭示细胞焦亡的抗肿瘤免疫功能
DOI：
10.1038/s41586-020-2079-1
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发表时间：
2020-03-11
期刊：
影响因子：
64.8
通讯作者：
Liu, Zhibo
中科院分区：
文献类型：
--
作者：
Wang, Qinyang;Wang, Yupeng;Liu, Zhibo
需要能够在活体动物中操作的生物正交化学来研究生物过程，例如细胞死亡和免疫。最近的研究已经确定了一个gasdermin家族的孔形成蛋白，执行炎性小体依赖性和非依赖性焦亡，-。Pyroptosis是促炎性的，但其对抗肿瘤免疫的影响尚不清楚。在这里，我们建立了一个生物正交化学系统，其中可以进入细胞的癌症成像探针苯丙氨酸三氟硼酸盐（Phe-BF 3）脱甲硅烷基化并“切割”含有甲硅烷基醚的设计接头。该系统使得能够在小鼠中从抗体-药物缀合物控制释放药物。当与纳米颗粒介导的递送结合时，Phe-BF 3催化的脱甲硅烷基化可以从纳米颗粒缀合物中释放客户蛋白质-包括活性gasdermin-选择性地进入小鼠肿瘤细胞。我们将该生物正交系统应用于gasdermin，其显示少于15%的肿瘤细胞的焦亡足以清除整个4 T1乳腺肿瘤移植物。肿瘤消退在免疫缺陷小鼠或T细胞耗竭后不存在，并且与增强的抗肿瘤免疫应答相关。注射减少的无效剂量的纳米颗粒结合gasdermin沿着Phe-BF 3使4 T1肿瘤对抗PD 1治疗敏感。因此，我们基于Phe-BF 3脱甲硅烷基化的生物正交系统是化学生物学的有力工具;我们对该系统的应用表明，热解诱导的炎症引发了强大的抗肿瘤免疫，并可与检查点阻断协同作用。
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-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-BF3could 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-BF3sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3desilylation 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.