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

Sci Immunol. 2020 Jan 17;5(43):eaax7969. 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 ⁸ ² ⁴

Affiliations

1 Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China.
2 Clinical Immunology Center, CAMS, Beijing 100005, China.
3 Biotherapy Center and Cancer Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
4 Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
5 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
6 Peking University People's Hospital, Peking University Institute of Hematology, Beijing 100044, China.
7 Department of Immunology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan 450008, China.
8 Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China. tjhuangbo@hotmail.com.

PMID: 31953257 DOI: 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.

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