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Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome.
Science Immunology ( IF 24.8 ) Pub Date : 2020-01-17 , DOI: 10.1126/sciimmunol.aax7969
Yuying Liu 1, 2 , Yiliang Fang 1 , Xinfeng Chen 3 , Zhenfeng Wang 1 , Xiaoyu Liang 1 , Tianzhen Zhang 1 , Mengyu Liu 1 , Nannan Zhou 1 , Jiadi Lv 1 , Ke Tang 4 , Jing Xie 1 , Yunfeng Gao 1 , Feiran Cheng 1 , Yabo Zhou 1 , Zhen Zhang 3 , Yu Hu 5 , Xiaohui Zhang 6 , Quanli Gao 7 , Yi Zhang 3 , Bo Huang 1, 2, 4
Affiliation  

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.

中文翻译:

加德明E介导的CAR T细胞介导的靶细胞热解触发细胞因子释放综合征。

细胞因子释放综合征(CRS)抵消了嵌合抗原受体(CAR)T细胞疗法在癌症患者中的有效性,但CRS的潜在机制仍不清楚。在这里,我们显示了肿瘤细胞的热解在CAR T细胞治疗期间触发了CRS。我们发现,CAR T细胞通过释放颗粒酶B迅速激活靶细胞中的半胱天冬酶3。后者裂解了Gasdermin E(GSDME),一种在B白血病和其他靶细胞中高度表达的成孔蛋白,导致大量的细胞凋亡。因此,解热释放因子激活胱天蛋白酶1的巨噬细胞中GSDMD裂解,从而导致细胞因子的释放和随后的CRS。敲除GSDME,消耗巨噬细胞或抑制caspase 1可消除CRS在小鼠模型中的发生。在患者中 GSDME和乳酸脱氢酶水平与CRS的严重程度相关。值得注意的是,我们发现,CAR T细胞而不是现有的CD8 + T细胞使用的穿孔素/粒酶B的数量对于CAR T细胞诱导靶细胞热解至关重要。
更新日期:2020-01-17
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