Editors' ChoiceCancer Immunology

Destroying tumors with pyroptosis

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Science Signaling  24 Mar 2020:
Vol. 13, Issue 624, eabb8244
DOI: 10.1126/scisignal.abb8244

Gasdermin E suppresses tumor growth by stimulating antitumor immunity in a pyroptosis-dependent manner.

Gasdermin proteins are cleaved by inflammatory caspases to generate N-terminal fragments that form pores in the plasma membrane, leading to proinflammatory cytokine release and cell death by pyroptosis. Gasdermin E (GSDME) can also be cleaved by caspase-3 at Asp270, which converts noninflammatory apoptotic signals into pyroptotic cell death. GSDME abundance is reduced in many cancers, and decreased GSDME correlates with poor survival in patients with breast cancer, suggesting that GSDME acts as a tumor suppressor. Zhang et al. found that 20 of 22 cancer-associated mutations in GSDME prevented GSDME from mediating pyroptosis in cells. In immunocompetent mice, GSDME-deficient tumor cells grew more rapidly than did tumor cells with endogenous GSDME. Moreover, the GSDME-deficient tumors had reduced numbers of infiltrating CD8+ T cells and natural killer (NK) cells. Conversely, tumors overexpressing wild-type GSDME grew more slowly and exhibited increased immune cell infiltration, effects not seen in tumors overexpressing loss-of-function GSDME mutants. Reduced tumor growth in the context of GSDME overexpression required NK cells and CD8+ T cells. Mice injected with GSDME-overexpressing tumor cells were protected from secondary tumor challenge. Coculture of NK cells and GSDME-expressing target cells resulted in pyroptosis, which depended on the release of cytotoxic granules from the NK cells and was only partially dependent on caspase-3. The protease granzyme B, which is found in NK cell granules, cleaved wild-type GSMDE but not a D270A mutant GSDME in vitro, and treatment of cells expressing wild-type GSDME with granzyme B and the pore-forming protein perforin resulted in pyroptosis. Lastly, compared with tumor cells overexpressing wild-type GSDME, tumor cells expressing the GSDME D270A mutant grew rapidly in mice and had reduced immune cell infiltration. Together, these data suggest that GSDME exerts a tumor-suppressive effect through the pyroptosis-dependent activation of antitumor immunity.

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