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.