期刊
HUMAN IMMUNOLOGY
卷 82, 期 2, 页码 130-138出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.humimm.2020.12.002
关键词
Mesothelin; Chimeric antigen receptor T; Programmed cell death protein 1; Short hairpin RNA; Immunotherapy
类别
资金
- Science and Technology Commission of Shanghai Municipality [19ZR1454700]
This study explores how PD-1-mediated T cell exhaustion affects the anti-tumor activity of MSLN-targeted CAR T cells, showing that silencing PD-1 significantly enhances CAR T cell cytokine production and cytotoxicity against cancer cells expressing PD-L1. It suggests the potential of targeting other specific genes involved in immune checkpoints to boost CART cell therapies against human tumors.
Chimeric antigen receptor T (CART) cell therapy is a new pillar in cancer therapeutics, and has been successfully used for the treatment of cancers, including acute lymphoblastic leukemia and solid cancers. Following immune attack, many tumors upregulate inhibitory ligands which bind to inhibitory receptors on T cells. For example, the interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands (widely known as PD-L1) on a target tumor limits the efficacy of CART cells therapy against poorly responding tumors. Here, we use mesothelin (MSLN)-expressing human ovarian cancer cells (SKOV3) and human colon cancer cells (HCT116) to investigate whether PD-1-mediated T cell exhaustion affects the anti-tumor activity of MSLN-targeted CAR T cells. We utilized cell-intrinsic PD 1-targeting shRNA overexpression strategy, resulting in a significant PD-1 silencing in CAR T cells. The reduction of PD-1 expression on T cell surface strongly augmented CAR T cell cytokine production and cytotoxicity towards PD-L1-expressing cancer cells in vitro. This study indicates the enhanced antitumor efficacy of PD-1-silencing MSLN-targeted CAR T cells against several cancers and suggests the potential of other specific gene silencing on the immune checkpoints to enhance the CART cell therapies against human tumors. (c) 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
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