Caspase-3 cleaves gasdermin E (GSDME) and converts noninflammatory apoptosis to inflammatory cell death (pyroptosis) in GSDME-expressing cells. GSDME expression is suppressed in many cancer lines and mutated in some others, and reduced GSDME is associated with metastasis and decreased survival in breast cancer, suggesting GSDME might be a tumor suppressor. Here we show reduced GSDME function of 7 of 8 tested cancer-associated mutations. Gsdme knockout in GSDME-expressing tumors enhances, while ectopic expression in Gsdme-repressed tumors inhibits, tumor growth. The GSDME tumor-suppressive effect is cell-extrinsic, mediated by cytotoxic lymphocyte killing and abrogated in perforin-deficient mice or mice lacking lymphocytes. GSDME expression enhances tumor-associated macrophage phagocytosis and the number and functions of tumor-infiltrating NK and CD8+ T lymphocytes. Killer cells also activate GSDME-mediated pyroptosis independently of caspase activation when Granzyme B directly cleaves GSDME at the same site as caspase-3 (Asp270). Thus, GSDME suppresses tumor growth by activating anti-tumor immunity.
Citation Format: Zhibin Zhang, Ying Zhang, Shiyu Xia, Qing Kong, Shunying Li, Xing Liu, Caroline Junqueira, James Ansara, Satyaki Sengupta, Yandan Yao, Hao Wu, Judy Lieberman. Gasdermin E suppresses tumor growth by activating antitumor immunity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A022. doi:10.1158/1535-7163.TARG-19-A022