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Strategies to package recombinant Adeno-Associated Virus expressing the N-terminal gasdermin domain for tumor treatment

Author

Listed:
  • Yuan Lu

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Wenbo He

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Xin Huang

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Yu He

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Xiaojuan Gou

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Xiaoke Liu

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Zhe Hu

    (Huazhong Agricultural University)

  • Weize Xu

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Khaista Rahman

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Shan Li

    (Huazhong Agricultural University)

  • Sheng Hu

    (Hubei Cancer Hospital, Huazhong Agricultural University)

  • Jie Luo

    (Taihe Hospital, Hubei University of Medicine)

  • Gang Cao

    (Huazhong Agricultural University
    Huazhong Agricultural University
    Huazhong Agricultural University)

Abstract

Pyroptosis induced by the N-terminal gasdermin domain (GSDMNT) holds great potential for anti-tumor therapy. However, due to the extreme cytoxicity of GSDMNT, it is challenging to efficiently produce and deliver GSDMNT into tumor cells. Here, we report the development of two strategies to package recombinant adeno-associated virus (rAAV) expressing GSDMNT: 1) drive the expression of GSDMNT by a mammal specific promoter and package the virus in Sf9 insect cells to avoid its expression; 2) co-infect rAAV-Cre to revert and express the double-floxed inverted GSDMNT. We demonstrate that these rAAVs can induce pyroptosis and prolong survival in preclinical cancer models. The oncolytic-viruses induce pyroptosis and evoke a robust immune-response. In a glioblastoma model, rAAVs temporarily open the blood-brain barrier and recruit tumor infiltrating lymphocytes into the brain. The oncolytic effect is further improved in combination with anti-PD-L1. Together, our strategies efficiently produce and deliver GSDMNT into tumor cells and successfully induce pyroptosis, which can be exploited for anti-tumor therapy.

Suggested Citation

  • Yuan Lu & Wenbo He & Xin Huang & Yu He & Xiaojuan Gou & Xiaoke Liu & Zhe Hu & Weize Xu & Khaista Rahman & Shan Li & Sheng Hu & Jie Luo & Gang Cao, 2021. "Strategies to package recombinant Adeno-Associated Virus expressing the N-terminal gasdermin domain for tumor treatment," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27407-0
    DOI: 10.1038/s41467-021-27407-0
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    References listed on IDEAS

    as
    1. Qinyang Wang & Yupeng Wang & Jingjin Ding & Chunhong Wang & Xuehan Zhou & Wenqing Gao & Huanwei Huang & Feng Shao & Zhibo Liu, 2020. "A bioorthogonal system reveals antitumour immune function of pyroptosis," Nature, Nature, vol. 579(7799), pages 421-426, March.
    2. Jingjin Ding & Kun Wang & Wang Liu & Yang She & Qi Sun & Jianjin Shi & Hanzi Sun & Da-Cheng Wang & Feng Shao, 2016. "Pore-forming activity and structural autoinhibition of the gasdermin family," Nature, Nature, vol. 535(7610), pages 111-116, July.
    3. Yupeng Wang & Wenqing Gao & Xuyan Shi & Jingjin Ding & Wang Liu & Huabin He & Kun Wang & Feng Shao, 2017. "Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin," Nature, Nature, vol. 547(7661), pages 99-103, July.
    4. Jianjin Shi & Yue Zhao & Kun Wang & Xuyan Shi & Yue Wang & Huanwei Huang & Yinghua Zhuang & Tao Cai & Fengchao Wang & Feng Shao, 2015. "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death," Nature, Nature, vol. 526(7575), pages 660-665, October.
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