Precise tumor immune rewiring via synthetic CRISPRa circuits gated by concurrent gain/loss of transcription factors

Yafeng Wang, Guiquan Zhang, Qingzhou Meng, Shisheng Huang, Panpan Guo, Qibin Leng, Lingyun Sun, Geng Liu (), Xingxu Huang () and Jianghuai Liu ()
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Yafeng Wang: Model Animal Research Center at Medical School of Nanjing University
Guiquan Zhang: Model Animal Research Center at Medical School of Nanjing University
Qingzhou Meng: Affiliated Cancer Hospital & Institute of Guangzhou Medical University
Shisheng Huang: ShanghaiTech University
Panpan Guo: The Affiliated Drum Tower Hospital of Nanjing University Medical School
Qibin Leng: Affiliated Cancer Hospital & Institute of Guangzhou Medical University
Lingyun Sun: The Affiliated Drum Tower Hospital of Nanjing University Medical School
Geng Liu: Model Animal Research Center at Medical School of Nanjing University
Xingxu Huang: ShanghaiTech University
Jianghuai Liu: Model Animal Research Center at Medical School of Nanjing University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Nevertheless, the precise delivery of immunotherapeutic activities to the tumors remains challenging. Here, we explore a synthetic gene circuit-based strategy for specific tumor identification, and for subsequently engaging immune activation. By design, these circuits are assembled from two interactive modules, i.e., an oncogenic TF-driven CRISPRa effector, and a corresponding p53-inducible off-switch (NOT gate), which jointly execute an AND-NOT logic for accurate tumor targeting. In particular, two forms of the NOT gate are developed, via the use of an inhibitory sgRNA or an anti-CRISPR protein, with the second form showing a superior performance in gating CRISPRa by p53 loss. Functionally, the optimized AND-NOT logic circuit can empower a highly specific and effective tumor recognition/immune rewiring axis, leading to therapeutic effects in vivo. Taken together, our work presents an adaptable strategy for the development of precisely delivered immunotherapy.

Date: 2022
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DOI: 10.1038/s41467-022-29120-y

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