title: CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer.
abstract: The successful use of immune cell checkpoint inhibitors PD-1 and PD-L1, over the past 5 y has raised the concern of using immunotherapy to treat various cancers. Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits high infiltration of lymphocytes and high amplification of immune-related genes including PD-L1 as distinguished from Epstein-Barr virus-non-associated gastric cancer (EBVnGC). Here, we presume that this PD-1/PD-L1 pathway may hinder the efficacy of adoptive T cell therapy toward EBVaGC. These studies reveal possibility of generating PD-1-disrupted CTL by CRISPR-Cas9 system and demonstrate enhanced immune response of these PD-1-disrupted CTLs to the EBV-LMP2A antigen and superior cytotoxicity to the EBV-positive gastric cancer cell. In addition, when combined with low-dose radiotherapy, these PD-1-disrupted CTLs mediated an impressive antitumor effect in a xenograft mouse model of EBVaGC. Taken together, these studies illustrate PD-1/PD-L1-mediated immune tolerance of EBVaGC and provide a new strategy for targeting immune checkpoints to break the tolerance for the T cell-based adoptive therapy.
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Su
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Zhengyun
authors.initials: Z
authors.lastname: Zou
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Fangjun
authors.initials: F
authors.lastname: Chen
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Naiqing
authors.initials: N
authors.lastname: Ding
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Pathology of Drum Tower Hospital, Medical School of Nanjing University , Nanjing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology of Drum Tower Hospital, Medical School of Nanjing University , Nanjing, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, National Resource Center for Mutant Mice , Nanjing, China.
authors.forename: Bian
authors.initials: B
authors.lastname: Hu
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Huizi
authors.initials: H
authors.lastname: Sha
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Fanyan
authors.initials: F
authors.lastname: Meng
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wei
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, National Resource Center for Mutant Mice, Nanjing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.affiliation: The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China.
authors.forename: Baorui
authors.initials: B
authors.lastname: Liu
keywords: Adoptive cell therapy; CRISPR; EBV-associated gastric cancer; checkpoint blockade