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

作者：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 · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-27407-0 · 被引用次数：50 · 研究领域：Virus-based gene therapy research、interferon and immune responses、Immune Cell Function and Interaction

Abstract Pyroptosis induced by the N-terminal gasdermin domain (GSDM NT ) holds great potential for anti-tumor therapy. However, due to the extreme cytoxicity of GSDM NT , it is challenging to efficiently produce and deliver GSDM NT into tumor cells. Here, we report the development of two strategies to package recombinant adeno-associated virus (rAAV) expressing GSDM NT : 1) drive the expression of GSDM NT 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 GSDM NT . 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 GSDM NT into tumor cells and successfully induce pyroptosis, which can be exploited for anti-tumor therapy.