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  2. Photo-Enhanced CRISPR/Cas9 System Enables Robust PD-L1 Gene Disruption in Cancer Cells and Cancer Stem-Like Cells for Efficient Cancer Immunotherapy

Photo-Enhanced CRISPR/Cas9 System Enables Robust PD-L1 Gene Disruption in Cancer Cells and Cancer Stem-Like Cells for Efficient Cancer Immunotherapy

  • Small. 2020 Dec 2;e2004879. doi: 10.1002/smll.202004879.
Liang Zhao 1 2 Yingli Luo 1 Qiaoyi Huang 1 Ziyang Cao 1 2 Xianzhu Yang 1 3
Affiliations

Affiliations

  • 1 Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, 510006, P. R. China.
  • 2 Key Laboratory of Biomedical Engineering of Guangdong Province and National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, P. R. China.
  • 3 Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, P. R. China.
Abstract

Blocking immune checkpoint pathways with an antibody or small interfering RNA (siRNA) has become a promising method to reactivate antitumor responses for Cancer treatment. However, both blockade strategies achieve only temporary inhibition of these immune checkpoints. Herein, a photoswitched CRISPR/Cas9 system for genomic disruption of the PD-L1 gene is developed to achieve permanent blockade of the PD-1/PD-L1 pathway; this system is constructed by using a photoactivated self-degradable polyethyleneimine derivative and the plasmid pX330/sgPD-L1 (expression of the Cas9 protein and single-guide RNA targeting PD-L1). Under LIGHT irradiation, this photoswitched CRISPR/Cas9 system efficiently genetically disrupts the PD-L1 gene in not only bulk Cancer cells but also Cancer stem-like cells. As a result, the photoswitched CRISPR/Cas9 system significantly increases the infiltration of CD8+ T cells into tumor tissue, leading to effective activation of a T cell-mediated antitumor response against Cancer cells and Cancer stem-like cells. This study provides an alternative strategy to block the PD-1/PD-L1 pathway for efficacious immune checkpoint therapy.

Keywords

PD‐1/PD‐L1 blockade; cancer immunotherapy; cancer stem‐like cells; photoactivated self‐degradable nanocomplex; photoswitched CRISPR/Cas9 system.

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