中國科學家探究焦亡的抗腫瘤免疫功能
作者：
小柯機器人發布時間：2020/3/16 14:26:23
北京大學劉志博和中國醫學科學院邵峰課題組合作取得一項新突破。他們開發的生物正交系統揭示了焦亡的抗腫瘤免疫功能。2020年3月11日的《自然》在線發表了這項成果。
在這項研究中，研究人員建立了一個生物正交化學系統。在該系統中，癌症成像探針苯丙氨酸三氟硼酸酯（Phe-BF3）可以進入細胞，使其脫甲矽烷基化並「裂解」成包含甲矽烷基醚的連接子。
該系統可以控制藥物從小鼠的抗體-藥物結合物中釋放。當與納米粒子介導的傳遞結合時，由Phe-BF3催化的去甲矽烷基化作用可以從納米粒子結合物中釋放一種乘客蛋白（包括活化的gasdermin），並選擇性地進入小鼠腫瘤細胞中。
將此生物正交系統應用於gasdermin，研究人員發現低於15％腫瘤細胞焦亡足以清除整個移植的4T1乳腺腫瘤。在免疫缺陷或T細胞耗竭的小鼠中沒有腫瘤抑制，並且這與抗腫瘤免疫反應增強相關。
注射降低劑量或無效劑量gasdermin與Phe-BF3結合的納米顆粒使4T1腫瘤對抗PD1治療敏感。因此，基於Phe-BF3脫甲矽烷基的生物正交系統是強大的化學生物學工具。在該系統上的應用表明，細胞焦亡誘導的炎症觸發了強大的抗腫瘤免疫力，並且可與檢查點封鎖協同作用。
據悉，需要能夠在活體動物中起作用的生物正交化學來研究生物學過程，例如細胞死亡和免疫。最近的研究發現了炎症小體依賴性和非依賴性的焦亡成孔蛋白gasdermin家族。細胞焦亡是促炎性的，但其對抗腫瘤免疫的作用尚不清楚。
附：英文原文
Title: A bioorthogonal system reveals antitumour immune function of pyroptosis
Author: Qinyang Wang, Yupeng Wang, Jingjin Ding, Chunhong Wang, Xuehan Zhou, Wenqing Gao, Huanwei Huang, Feng Shao, Zhibo Liu
Issue&Volume: 2020-03-11
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. 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.
DOI: 10.1038/s41586-020-2079-1
Source: https://www.nature.com/articles/s41586-020-2079-1