Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome
- 3 January 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Immunology
- Vol. 5 (43)
- https://doi.org/10.1126/sciimmunol.aax7969
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.Keywords
Funding Information
- National Natural Science Foundation of China (81788101, 81661128007, 81530080)
- National Natural Science Foundation of China (81773062)
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