CD81 通过阻断 CD274/PD-L1 的选择性自噬降解驱动放射抵抗性胶质母细胞瘤的免疫逃逸
CD81 drives immune evasion in radioresistant glioblastoma by blocking selective autophagic degradation of CD274/PD-L1.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
包装表达 N 端 gasdermin 结构域的重组腺相关病毒用于肿瘤治疗的策略
英文原题：Strategies to package recombinant Adeno-Associated Virus expressing the N-terminal gasdermin domain for tumor treatment.
查看英文原题
Strategies to package recombinant Adeno-Associated Virus expressing the N-terminal gasdermin domain for tumor treatment.
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中文摘要
N端gasdermin结构域（GSDM NT）诱导的细胞焦亡在抗肿瘤治疗中具有巨大潜力。然而，由于GSDM NT的极端细胞毒性，高效生产和递送GSDM NT进入肿瘤细胞具有挑战性。在此，我们报道了两种包装表达GSDM NT的重组腺相关病毒（rAAV）的策略：1）通过哺乳动物特异性启动子驱动GSDM NT的表达，并在Sf9昆虫细胞中包装病毒以避免其表达；2）共感染rAAV-Cre以逆转并表达双floxed倒置的GSDM NT。我们证明这些rAAV可在临床前癌症模型中诱导细胞焦亡并延长生存期。溶瘤病毒诱导细胞焦亡并引发强烈的免疫反应。在胶质母细胞瘤模型中，rAAV暂时打开血脑屏障并招募TIL（肿瘤浸润淋巴细胞）进入脑内。与抗PD-L1联合使用时，溶瘤效果进一步提高。总之，我们的策略高效地生产并将GSDM NT递送至肿瘤细胞，成功诱导细胞焦亡，可用于抗肿瘤治疗。
展开英文摘要原文
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.
论文信息
- 作者
- Lu Y、He W、Huang X、He Y、Gou X、Liu X、Hu Z、Xu W
- 第一作者单位
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Huazhong Agricultural University, 430070, Wuhan, China.China
- 通讯作者单位
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Huazhong Agricultural University, 430070, Wuhan, China. gcao@mail.hzau.edu.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Nature communications2021 Dec 9
- 原文标识
- PubMed 34887423 · DOI 10.1038/s41467-021-27407-0
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