CRISPR knock out of programmed cell death protein 1 enhances anti-tumor activity of cytotoxic T lymphocytes
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Zhilong Zhao1, Long Shi2, Wei Zhang4, Jinsheng Han5, Shaohui Zhang6, Zexian Fu7 and Jianhui Cai1,3
1Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei, China
2Department of Oncology, Hebei Medical University Second Affiliated Hospital, Shijiazhuang, Hebei, China
3Department of Surgery & Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China
4Department of Surgery, Handan Central Hospital, Handan, Hebei, China
5Department of Surgery, Cangzhou Hospital of Traditional Chinese Medicine and Western Medicine Integrated Hebei, Cangzhou, Hebei, China
6Department of Oncology, Hebei Medical University Third Affiliated Hospital, Shijiazhuang, Hebei, China
7Department of Oncology, Hebei University of Engineering Affiliated Hospital, Baoding, Hebei, China
Jianhui Cai, email: [email protected]
Keywords: anti-tumor immunity; CRISPR; cytotoxic T lymphocyte; immune checkpoint; PD-1
Received: July 18, 2017 Accepted: August 27, 2017 Published: December 27, 2017
Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that functions to attenuate T cell activation. In this study, we knocked out (KO) PD-1 in cytotoxic T lymphocytes (CTLs) using CRISPR-Cas9 system to evaluate its effect on the anti-tumor activity of the CTLs against multiple myeloma (MM). Results show that PD-1 KO CTLs facilitate apoptosis and caspase activation of the co-cultured MM cells and enhanced MM cell death by 36% compared with the control. PD-1 KO also increased TNF-α and IFN-γ secretion of the CTLs by 2.4 and 1.9-fold respectively. The effectiveness of PD-1 KO in enhancing anti-tumor activity of the CTLs was verified in vivo using mouse xenograft model. The xenografted mice treated with PD-1 KO CTLs demonstrated repressed MM tumor growth and prolonged survival compared with the control group. We conclude that CRISPR-Cas9 is an efficient system to knock out PD-1 from CTLs and PD-1 KO could significantly enhance the anti-tumor activity of CTLs.
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