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. [email protected].

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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