小柯机器人

中国科学家探究焦亡的抗肿瘤免疫功能
2020-03-16 14:26

北京大学刘志博和中国医学科学院邵峰课题组合作取得一项新突破。他们开发的生物正交系统揭示了焦亡的抗肿瘤免疫功能。2020年3月11日的《自然》在线发表了这项成果。

在这项研究中,研究人员建立了一个生物正交化学系统。在该系统中,癌症成像探针苯丙氨酸三氟硼酸酯(Phe-BF3)可以进入细胞,使其脱甲硅烷基化并“裂解”成包含甲硅烷基醚的连接子。

该系统可以控制药物从小鼠的抗体-药物结合物中释放。当与纳米粒子介导的传递结合时,由Phe-BF3催化的去甲硅烷基化作用可以从纳米粒子结合物中释放一种乘客蛋白(包括活化的gasdermin),并选择性地进入小鼠肿瘤细胞中。

将此生物正交系统应用于gasdermin,研究人员发现低于15%肿瘤细胞焦亡足以清除整个移植的4T1乳腺肿瘤。在免疫缺陷或T细胞耗竭的小鼠中没有肿瘤抑制,并且这与抗肿瘤免疫反应增强相关。

注射降低剂量或无效剂量gasdermin与Phe-BF3结合的纳米颗粒使4T1肿瘤对抗PD1治疗敏感。因此,基于Phe-BF3脱甲硅烷基的生物正交系统是强大的化学生物学工具。在该系统上的应用表明,细胞焦亡诱导的炎症触发了强大的抗肿瘤免疫力,并且可与检查点封锁协同作用。

据悉,需要能够在活体动物中起作用的生物正交化学来研究生物学过程,例如细胞死亡和免疫。最近的研究发现了炎症小体依赖性和非依赖性的焦亡成孔蛋白gasdermin家族。细胞焦亡是促炎性的,但其对抗肿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

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0