Kobayashi Eiji, Kishi Hiroyuki, Ozawa Tatsuhiko, Hamana Hiroshi, Nakagawa Hidetoshi, Jin Aishun, Lin Zhezhu, Muraguchi Atsushi
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Biochem Biophys Res Commun. 2014 Oct 31;453(4):798-803. doi: 10.1016/j.bbrc.2014.10.024. Epub 2014 Oct 14.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its associated receptors (TRAIL-R/TR) are attractive targets for cancer therapy because TRAIL induces apoptosis in tumor cells through TR while having little cytotoxicity on normal cells. Therefore, many agonistic monoclonal antibodies (mAbs) specific for TR have been produced, and these induce apoptosis in multiple tumor cell types. However, some TR-expressing tumor cells are resistant to TR-specific mAb-induced apoptosis. In this study, we constructed a chimeric antigen receptor (CAR) of a TRAIL-receptor 1 (TR1)-specific single chain variable fragment (scFv) antibody (TR1-scFv-CAR) and expressed it on a Jurkat T cell line, the KHYG-1 NK cell line, and human peripheral blood lymphocytes (PBLs). We found that the TR1-scFv-CAR-expressing Jurkat cells killed target cells via TR1-mediated apoptosis, whereas TR1-scFv-CAR-expressing KHYG-1 cells and PBLs killed target cells not only via TR1-mediated apoptosis but also via CAR signal-induced cytolysis, resulting in cytotoxicity on a broader range if target cells than with TR1-scFv-CAR-expressing Jurkat cells. The results suggest that TR1-scFv-CAR could be a new candidate for cancer gene therapy.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）及其相关受体（TRAIL-R/TR）是癌症治疗的有吸引力的靶点，因为TRAIL通过TR在肿瘤细胞中诱导凋亡，而对正常细胞几乎没有细胞毒性。因此，已经产生了许多针对TR的激动性单克隆抗体（mAb），并且这些抗体在多种肿瘤细胞类型中诱导凋亡。然而，一些表达TR的肿瘤细胞对TR特异性mAb诱导的凋亡具有抗性。在本研究中，我们构建了一种TRAIL受体1（TR1）特异性单链可变片段（scFv）抗体的嵌合抗原受体（CAR）（TR1-scFv-CAR），并在Jurkat T细胞系、KHYG-1 NK细胞系和人外周血淋巴细胞（PBL）上表达。我们发现，表达TR1-scFv-CAR的Jurkat细胞通过TR1介导的凋亡杀死靶细胞，而表达TR1-scFv-CAR的KHYG-1细胞和PBL不仅通过TR1介导的凋亡杀死靶细胞，还通过CAR信号诱导的细胞溶解杀死靶细胞，从而对靶细胞产生比表达TR1-scFv-CAR的Jurkat细胞更广泛的细胞毒性。结果表明，TR1-scFv-CAR可能是癌症基因治疗的新候选物。
