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细胞焦亡是细胞程序性死亡方式之一，属于天然免疫反应，细胞焦亡时不断胀大直至细胞膜破裂，继而释放大量促炎症因子，进而激活抗感染或抗肿瘤免疫力。高度炎症性细胞焦亡通常比生理性主动自发细胞凋亡发生得更快。上皮细胞增殖分化蛋白GSDM被分解时可以产生成孔氨基末端片段，引起炎症性细胞焦亡。其中，由GSDME基因编码的家族遗传性衰老相关听力障碍蛋白DFNA5，属于GSDM蛋白质家族六大成员之一。GSDME基因突变产生的GSDME蛋白可被胱天蛋白酶3分解，从而将表达GSDME细胞的非炎症性凋亡转化为炎症性焦亡。许多癌症的GSDME表达都受到抑制，而GSDME水平降低的乳腺癌患者生存率显著较低，表明GSDME可能是一种肿瘤抑制蛋白。 2020年3月11日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表美国哈佛大学医学院、波士顿儿童医院、达纳法伯癌症研究所、中国中山大学孙逸仙纪念医院、中国科学院上海巴斯德研究所、巴西奥斯瓦尔多·克鲁兹基金会勒内·拉乔研究所、墨西哥国立自治大学、中国香港城市大学的研究报告，发现了GSDME通过激活抗肿瘤免疫力抑制三阴性乳腺癌等肿瘤生长的关键机制。 该研究对22种癌症相关GSDME基因突变进行检测，发现其中20种基因突变的GSDME功能减弱。通过基因同源重组技术，将GSDME基因异位表达小鼠的三阴性乳腺癌、结直肠癌、神经母细胞瘤GSDME基因剔除以后，可以抑制肿瘤生长。该肿瘤抑制作用由杀伤型淋巴细胞引起，对于穿孔蛋白缺乏或杀伤型淋巴细胞耗尽的小鼠，该抑制作用被消除。GSDME表达可以增强肿瘤相关巨噬细胞对肿瘤细胞的吞噬作用，同时增加肿瘤浸润自然杀伤型淋巴细胞、CD8阳性T淋巴细胞的数量和功能。杀伤型淋巴细胞颗粒酶B还可以在与胱天蛋白酶3相同的部位直接分解GSDME，从而激活不依赖于胱天蛋白酶的靶细胞焦亡。此外，无法分解或穿孔蛋白缺乏的GSDME蛋白无法抑制肿瘤。 因此，该研究结果表明，肿瘤抑制蛋白GSDME通过激活焦亡可以增强对三阴性乳腺癌等肿瘤的免疫力，下一步或将探讨上调GSDME水平的治疗策略，例如利用现有已被批准治疗白血病和骨髓增生异常的DNA甲基化抑制剂地西他滨。 Nature. 2020 Mar 11. [Epub ahead of print] Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Zhibin Zhang, Ying Zhang, Shiyu Xia, Qing Kong, Shunying Li, Xing Liu, Caroline Junqueira, Karla F. Meza-Sosa, Temy Mo Yin Mok, James Ansara, Satyaki Sengupta, Yandan Yao, Hao Wu, Judy Lieberman. Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China; René Rachou Institute, Oswaldo Cruz Foundation, Belo Horizonte, Brazil; Universidad Nacional Autónoma de México, Cuernavaca, Mexico; City University of Hong Kong, Hong Kong, Hong Kong. Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis). Gasdermin E (GSDME, also known as DFNA5)—mutated in familial ageing-related hearing loss—can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer, suggesting that GSDME might be a tumour suppressor. Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes: it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as the number and functions of tumour-infiltrating natural-killer and CD8+ T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity. SUBJECTS: Cell death and immune response, Inflammasome, NK cells, Tumour immunology, Tumour-suppressor proteins DOI: 10.1038/s41586-020-2071-9
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