嵌合抗原受体
化学
细胞毒性
抗原
聚糖
癌症研究
癌细胞
癌症免疫疗法
免疫疗法
癌症
分子生物学
生物化学
免疫学
生物
体外
遗传学
糖蛋白
作者
Jin-Yi Hyeon,Eun‐Su Kim,Hyeong Ji Lee,Young‐Ho Lee,Jeonghyun Lee,Eunha Kim,Chan Hyuk Kim
标识
DOI:10.1021/acs.jmedchem.3c00048
摘要
T cells expressing chimeric antigen receptors (CAR-T cells) have shown unprecedented clinical responses against hematological malignancies. However, some patients relapse after CAR-T cell therapy due to antigen-negative escape variants. Additionally, CAR-T cell therapies showed limited clinical efficacy in solid tumors with high antigen heterogeneity. To overcome this, we metabolically labeled the glycans on cancer cells to redirect CAR-T cell cytotoxicity regardless of the endogenous antigen expression status of the cancer cells. We found that modifying cancer cells with N-azidoacetylmannosamine and bicyclo[6.1.0]non-4-yne-fluorescein isothiocyanate can elicit selective and durable cytotoxicity of anti-FITC CAR-T cells. Furthermore, we demonstrated that dinitrophenyl-conjugated sialic acid (Sia-DNP) generated DNP-modified glycans on cancer cells in situ that could be effectively targeted by anti-DNP CAR-T cells to eradicate established tumors in xenograft models. Our study illustrates that metabolic glycan labeling using unnatural sugars can be combined with CAR-T cell therapy to provide novel cancer immunotherapy for solid tumors that lack viable target antigens.
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