| First Author | Shi L | Year | 2017 |
| Journal | Gene | Volume | 636 |
| Pages | 36-41 | PubMed ID | 28888577 |
| Mgi Jnum | J:254558 | Mgi Id | MGI:6100399 |
| Doi | 10.1016/j.gene.2017.09.010 | Citation | Shi L, et al. (2017) CRISPR knock out CTLA-4 enhances the anti-tumor activity of cytotoxic T lymphocytes. Gene 636:36-41 |
| abstractText | T cell-mediated anti-tumor immunity plays a pivotal role in cancer immune surveillance. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a protein receptor mainly expressed in activated T cells and regulatory T cells. CTLA-4 competes with CD28 for ligand binding and generates inhibitory signals to attenuate T cell activation. The blockade of CTLA-4 mediated immune inhibitory checkpoint has been associated with enhanced anti-tumor immunity. In this study, we use CRISPR-Cas9 system to knock out (KO) CTLA-4 from cytotoxic T lymphocytes (CTLs) and evaluate its effect on the anti-tumor activity of the CTLs. CTLA-4 KO CTLs robustly enhanced tumor cell death by 40% compared to the control and facilitated apoptosis and caspase activities in tumor cells. The knockout of CTLA-4 also increased TNF-alpha and IFN-gamma secretion of the CTLs by approximately 2-fold. The effectiveness of CTLA-4 KO in enhancing anti-tumor activity of the CTLs was verified in vivo using mouse xenograft model. The xenografted mice treated with CTLA-4 KO CTLs demonstrated repressed tumor growth and prolonged survival compared to the control group. Our data suggest that CRISPR targeting CTLA-4 immune checkpoint could significantly improve the anti-tumor activity of CTLs. |
