knocking out mediated by CRISPR-Cas9 genome editing for PD-L1 attenuation and enhanced antitumor immunity.
10.1016/j.apsb.2019.07.004
- Author:
Huan DENG
1
;
Songwei TAN
1
;
Xueqin GAO
1
;
Chenming ZOU
1
;
Chenfeng XU
1
;
Kun TU
1
;
Qingle SONG
1
;
Fengjuan FAN
2
;
Wei HUANG
3
;
Zhiping ZHANG
1
Author Information
1. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
2. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
3. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
- Publication Type:Journal Article
- Keywords:
Antitumor immunity;
CRISPR-Cas9 genome editing system;
Cyclin-dependent kinase 5 (Cdk5);
Nanoparticles;
Programmed death-ligand 1 (PD-L1)
- From:
Acta Pharmaceutica Sinica B
2020;10(2):358-373
- CountryChina
- Language:English
-
Abstract:
Blocking the programmed death-ligand 1 (PD-L1) on tumor cells with monoclonal antibody therapy has emerged as powerful weapon in cancer immunotherapy. However, only a minority of patients presented immune responses in clinical trials. To develop an alternative treatment method based on immune checkpoint blockade, we designed a novel and efficient CRISPR-Cas9 genome editing system delivered by cationic copolymer aPBAE to downregulate PD-L1 expression on tumor cells specifically knocking out Cyclin-dependent kinase 5 () gene . The expression of PD-L1 on tumor cells was significantly attenuated by knocking out , leading to effective tumor growth inhibition in murine melanoma and lung metastasis suppression in triple-negative breast cancer. Importantly, we demonstrated that aPBAE/Cas9-Cdk5 treatment elicited strong T cell-mediated immune responses in tumor microenvironment that the population of CD8 T cells was significantly increased while regulatory T cells (Tregs) was decreased. It may be the first case to exhibit direct PD-L1 downregulation CRISPR-Cas9 genome editing technology for cancer therapy. It will provide promising strategy for preclinical antitumor treatment through the combination of nanotechnology and genome engineering.
