Gasdermin E suppresses tumour growth by activating anti-tumour immunity

Abstract

Cleavage of the gasdermins to produce a pore-forming N-terminal fragment causes inflammatory death (pyroptosis) 1 . Caspase-3 cleaves gasdermin E (GSDME, also known as DFNA5), mutated in familial aging-related hearing loss 2 , which converts noninflammatory apoptosis to pyroptosis in GSDME-expressing cells 3 – 5 . GSDME expression is suppressed in many cancers and reduced GSDME is associated with decreased breast cancer survival 2 , 6 , suggesting GSDME might be a tumor suppressor. Here we show reduced GSDME function of 20 of 22 tested cancer-associated mutations. Gsdme knockout in GSDME-expressing tumors enhances, while ectopic expression in Gsdme -repressed tumors inhibits, tumor growth. Tumor suppression is mediated by cytotoxic lymphocyte killing since it is abrogated in perforin-deficient or killer lymphocyte-depleted mice. GSDME expression enhances tumor-associated macrophage phagocytosis and the number and functions of tumor-infiltrating NK 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. Non-cleavable or pore-defective GSDME are not tumor suppressive. Thus, tumor GSDME is a tumor suppressor by activating pyroptosis, which enhances anti-tumor immunity.

RETRACTED: Exosome-Delivered LncHEIH Promotes Gastric Cancer Progression by Upregulating EZH2 and Stimulating Methylation of the GSDME Promoter

“…As a previous study reported, the expression of GSDME is downregulated, and such deficiency can be restored when gastric cancer cells are treated with a methyltransferase inhibitor ( Akino et al, 2006 ). Moreover, as a tumor suppressor gene, GSDME has been declared to inhibit tumor progression in breast cancer, gastric cancer and CRC by activating antitumor immunity or inhibiting colony formation and cell proliferation ( Zhang et al, 2020 ). Thus, the increased methylation level of the GSDME promoter regulated by EZH2 may be important for the development of gastric cancer.…”

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

“…Recent studies have found that both killer-cell granzyme B and caspase-3 use cleavage at D270 to activate GSDME, induce tumor cells pyroptosis, enhance anti-tumor immunity, and exert tumor suppression effects. The expression of GSDME enhances the phagocytic function of tumor-associated macrophages on tumor cells, and enhances the number and functions of tumor-infiltrating NK cells and CD8 + T cells 70 , 71 . Similar studies have also found that granzyme A in cytotoxic lymphocytes can cleave the GSDMB of tumor cells to induce pyroptosis 72 , 73 .…”

Therapeutic modulation of inflammasome pathways

“…This study centers on the experimental broad-spectrum DPP inhibitor BXCL701 (also named VbP, PT-100, or Talabostat) that was recently assigned orphan drug designation for the treatment of AML by the FDA, and is based on recent findings showing that VbP/BXCL701 and more selective DPP8/DPP9 inhibitors are potent inducers of pyroptosis in AML cell lines and in primary AML samples from patients. 164 Several recent studies showed that enforced activation of Gasdermin family members in cancer cells enhanced immune cell-mediated tumor clearance in mouse models, [165][166][167] adding credence to the notion that pyroptosis induction may enhance cancer immunotherapies to the benefit of patients.…”