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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 7155 (12 09 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34887423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• GSDMA protein, human
• Neoplasm Proteins

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, physiopathology, therapy)
• Cell Line, Tumor
• Dependovirus (genetics, physiology)
• Female
• Glioblastoma (genetics, immunology, physiopathology, therapy)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins (genetics, immunology)
• Oncolytic Virotherapy
• Oncolytic Viruses (genetics, physiology)
• Pyroptosis
• Rats
• Rats, Wistar
• Sf9 Cells
• Viral Genome Packaging