美国加州大学旧金山分校Wendell A. Lim研究小组开发出一种新的T细胞回路,能够以超灵敏的阈值感应抗原密度。2021年2月25日,《科学》杂志在线发表了这项成果。
受自然超敏反应回路的启发,研究人员设计了两步式正反馈回路,该回路可让T细胞根据抗原密度阈值来区分靶标。在该回路中,HER2的低亲和力合成Notch受体控制HER2的高亲和力嵌合抗原受体(CAR)的表达。因此,增加HER2密度对T细胞具有协同作用,即增加了CAR表达和激活。
在体外和体内,具有这种回路的T细胞在表达正常量HER2的靶细胞和表达HER2100倍以上的癌细胞之间有着明显的区别。
据介绍,过表达的肿瘤相关抗原(例如HER2和表皮生长因子受体)是治疗性T细胞的潜在靶标,但CAR T细胞可能与表达低水平靶标抗原的正常组织发生毒性“非肿瘤”交叉反应。
附:英文原文
Title: T cell circuits that sense antigen density with an ultrasensitive threshold
Author: Rogelio A. Hernandez-Lopez, Wei Yu, Katelyn A. Cabral, Olivia A. Creasey, Maria del Pilar Lopez Pazmino, Yurie Tonai, Arsenia De Guzman, Anna Mkel, Kalle Saksela, Zev J. Gartner, Wendell A. Lim
Issue&Volume: 2021/02/25
Abstract: AbstractOverexpressed tumor associated antigens (e.g., HER2 and epidermal growth factor receptor) are attractive targets for therapeutic T cells, but toxic “off-tumor” cross-reaction with normal tissues expressing low levels of target antigen can occur with Chimeric Antigen Receptor (CAR) T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive feedback circuit that allows T cells to discriminate targets based on a sigmoidal antigen density threshold. In this circuit, a low affinity synthetic Notch receptor for HER2 controls the expression of a high affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells—it both increases CAR expression and activation—leading to a sigmoidal response. T cells with this circuit show sharp discrimination between target cells expressing normal amounts of HER2 and cancer cells expressing 100-fold more HER2, both in vitro and in vivo.
DOI: 10.1126/science.abc1855
Source: https://science.sciencemag.org/content/early/2021/02/24/science.abc1855