Cdk5 knocking out mediated by CRISPR-Cas9 genome editing for PD-L1 attenuation and enhanced antitumor immunity

• 来源期刊: 药学学报（英文版）
• 关键词: CRISPR-Cas9 genome editing system Cyclin-dependent kinase 5(Cdk5) Programmed death-ligand 1 (PD-L1) Antitumor immunity Nanoparticles
• 年，卷（期）: 2020,（2）
• 页码范围: 358-373
• 页数: 16页
• 语种: 英文

摘要

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 via specifically knocking out Cyclin-dependent kinase 5 (Cdk5) gene in vivo.The expression of PD-L1 on tumor cells was significantly attenuated by knocking out Cdk5,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 ofCD8+ T cells was significantly increased while regulatory T cells (Tregs) was decreased.It may be the first case to exhibit direct in vivo PD-L1 downregulation via 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.