Gasdermin E suppresses tumour growth by activating anti-tumour immunity

Nature. 2020 Mar;579(7799):415-420. doi: 10.1038/s41586-020-2071-9.

Zhibin Zhang ^# ¹ ², Ying Zhang ^# ³ ⁴, Shiyu Xia ³ ⁵, Qing Kong ⁶ ⁷, Shunying Li ⁸, Xing Liu ³ ⁴ ⁹, Caroline Junqueira ³ ⁴ ¹⁰, Karla F Meza-Sosa ³ ⁴ ¹¹, Temy Mo Yin Mok ³ ⁴ ¹², James Ansara ³ ⁴, Satyaki Sengupta ⁴ ¹³, Yandan Yao ⁸, Hao Wu ³ ⁵, Judy Lieberman ¹⁴ ¹⁵

Affiliations

1 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. zhibin.zhang@childrens.harvard.edu.
2 Department of Pediatrics, Harvard Medical School, Boston, MA, USA. zhibin.zhang@childrens.harvard.edu.
3 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
4 Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
6 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
7 Department of Genetics, Harvard Medical School, Boston, MA, USA.
8 Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
9 The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
10 René Rachou Institute, Oswaldo Cruz Foundation, Belo Horizonte, Brazil.
11 Laboratorio de Neuroimmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico.
12 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong.
13 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
14 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. judy.lieberman@childrens.harvard.edu.
15 Department of Pediatrics, Harvard Medical School, Boston, MA, USA. judy.lieberman@childrens.harvard.edu.
# Contributed equally.

PMID: 32188940 DOI: 10.1038/s41586-020-2071-9

Abstract

Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (Pyroptosis)¹. Gasdermin E (GSDME, also known as DFNA5)-mutated in familial ageing-related hearing loss²-can be cleaved by Caspase 3, thereby converting noninflammatory Apoptosis to Pyroptosis in GSDME-expressing cells^3-5. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast Cancer^2,6, 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.

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