Structure-based rational design of a novel chimeric PD1-NKG2D receptor for natural killer cells. (October 2019)

• Record Type: Journal Article
• Authors: Guo, Changjiang; Wang, Xiaoyin; Zhang, Huiyong; Zhi, Lingtong; Lv, Tanyu; Li, Mingfeng; Lu, Chengui; Zhu, Wuling
• Is Part Of: Molecular immunology. Volume 114(2019:Oct.)
• Page Start: 108
• Page End: 113
• Publication Date: 2019-10
• Subjects: CAR chimeric antigen receptor -- EC extracellular -- TM transmembrane -- CP cytoplasmic; Chimeric receptor -- Structure modeling -- Rational design -- PD-1 -- NKG2D -- Cytotoxicity; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2019.07.009
• Languages: English
• ISSNs: 0161-5890

Abstract

Graphical abstract: Highlights: Precise 3D structure modeling of transmembrane proteins is developed. NK cell-tailored chimeric receptors are rationally designed with NKG2D signaling. PNBB-NK92 cells demonstrate in vitro cytotoxicity against various tumor cells. Abstract: Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have the potential to provide the potential for the implementation of allogeneic "off-the-shelf" cellular therapy against cancers. Currently, most CARs are not optimized for NK cells, so new NK-tailored CARs are needed. Here, a major activating receptor of NK cells, NKG2D was harnessed to design different chimeric receptors that mediate strong NK cell signaling. In these NKG2D signaling-based chimeric receptors, the extracellular domain of inhibitory receptor PD-1 was employed to reverse the immune escape mediated by PD-1 ligands in the solid tumors. To achieve the rational design of chimeric PD1-NKG2D receptors, we developed a transmembrane protein tertiary structure prediction program (PredMP & I-TASSER) and optimized the conformation of the PD-1 ectodomain by genetically altering the sequences encoding the hinge and intracellular domain. Finally, we identified a chimeric PD1-NKG2D receptor containing NKG2D hinge region and 4-1BB co-stimulatory domain to exhibit stable surface expression and mediate in vitro cytotoxicity of NK92 cells against various tumor cells. This strategy now provides a promising approach for the computer-aided design (CAD) of potent NK cell-tailored chimeric receptors with NKG2D signaling.