Research ArticleIMMUNOTHERAPY

Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome

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Science Immunology  17 Jan 2020:
Vol. 5, Issue 43, eaax7969
DOI: 10.1126/sciimmunol.aax7969

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Gasdermin E as troublemaker

Cytokine release syndrome (CRS) is a complication associated with chimeric antigen receptor (CAR) T cell therapy in cancer patients. The mechanisms that trigger CRS are not clear, but Liu et al. describe a role for the pore-forming protein gasdermin E (GSDME) during tumor cell pyroptosis, which contributes to CRS. CAR T cells release granzyme B, which activates caspase 3 and cleaves GSDME in target tumor cells and causes pyroptosis. Pyroptosis by GSDME leads to activation of caspase 1 and GSDMD in macrophages, which is critical for triggering CRS. Elevated levels of GSDME in cancer patients positively correlated to CRS severity. In addition, the ability of CAR T cells to induce pyroptosis is associated with the levels of perforin and granzyme B released.

Abstract

Cytokine release syndrome (CRS) counteracts the effectiveness of chimeric antigen receptor (CAR) T cell therapy in cancer patients, but the mechanism underlying CRS remains unclear. Here, we show that tumor cell pyroptosis triggers CRS during CAR T cell therapy. We find that CAR T cells rapidly activate caspase 3 in target cells through release of granzyme B. The latter cleaves gasdermin E (GSDME), a pore-forming protein highly expressed in B leukemic and other target cells, which results in extensive pyroptosis. Consequently, pyroptosis-released factors activate caspase 1 for GSDMD cleavage in macrophages, which results in the release of cytokines and subsequent CRS. Knocking out GSDME, depleting macrophages, or inhibiting caspase 1 eliminates CRS occurrence in mouse models. In patients, GSDME and lactate dehydrogenase levels are correlated with the severity of CRS. Notably, we find that the quantity of perforin/granzyme B used by CAR T cells rather than existing CD8+ T cells is critical for CAR T cells to induce target cell pyroptosis.

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