Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome
2020; American Association for the Advancement of Science; Volume: 5; Issue: 43 Linguagem: Inglês
10.1126/sciimmunol.aax7969
ISSN2470-9468
AutoresYuying Liu, Yiliang Fang, Xinfeng Chen, Zhenfeng Wang, Xiaoyu Liang, Tianzhen Zhang, Mengyu Liu, Nannan Zhou, Jiadi Lv, Ke Tang, Jing Xie, Yunfeng Gao, Feiran Cheng, Yabo Zhou, Zhen Zhang, Yu Hu, Xiaohui Zhang, Quanli Gao, Yi Zhang, Bo Huang,
Tópico(s)Hematopoietic Stem Cell Transplantation
ResumoCytokine 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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