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Photo‐Enhanced CRISPR/Cas9 System Enables Robust PD‐L1 Gene Disruption in Cancer Cells and Cancer Stem‐Like Cells for Efficient Cancer Immunotherapy
Author(s) -
Zhao Liang,
Luo Yingli,
Huang Qiaoyi,
Cao Ziyang,
Yang Xianzhu
Publication year - 2020
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.202004879
Subject(s) - crispr , immune checkpoint , cancer research , cancer cell , cas9 , cancer , cancer immunotherapy , immune system , cancer stem cell , biology , immunotherapy , gene , immunology , genetics
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.