T cell circuits that sense antigen density with an ultrasensitive threshold

doi:10.1126/science.abc1855

GSTDTAP > 气候变化

DOI	10.1126/science.abc1855
	T cell circuits that sense antigen density with an ultrasensitive threshold
	Rogelio A. Hernandez-Lopez; Wei Yu; Katelyn A. Cabral; Olivia A. Creasey; Maria del Pilar Lopez Pazmino; Yurie Tonai; Arsenia De Guzman; Anna Mäkelä; Kalle Saksela; Zev J. Gartner; Wendell A. Lim
	2021-03-12
发表期刊	Science
出版年	2021
英文摘要	Biological signaling systems can exhibit a large, nonlinear—or “ultrasensitive”—response, which would be useful to engineer into therapeutic T cells to allow for better discrimination between cancer cells and normal tissues. Hernandez-Lopez et al. modified human T cells using a two-step mechanism that allowed them to kill cells expressing large amounts of cancer marker protein but not cells expressing a small amount of the same protein. A first synthetic receptor recognized the antigen with low affinity. That receptor signaled to increase expression of a chimeric antigen receptor (CAR) with high affinity for the same antigen. The circuit proved effective in cell culture and mouse cancer models, offering hope of extending the CAR T cell strategy against solid tumors. Science , this issue p. [1166][1] Overexpressed tumor-associated antigens [for example, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)] are attractive targets for therapeutic T cells, but toxic “off-tumor” cross-reaction with normal tissues that express 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 human cytotoxic T cells to discriminate targets on the basis of 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 increases both 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 times as much HER2, both in vitro and in vivo. [1]: /lookup/doi/10.1126/science.abc1855
领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/318699
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Rogelio A. Hernandez-Lopez,Wei Yu,Katelyn A. Cabral,et al. T cell circuits that sense antigen density with an ultrasensitive threshold[J]. Science,2021.
APA	Rogelio A. Hernandez-Lopez.,Wei Yu.,Katelyn A. Cabral.,Olivia A. Creasey.,Maria del Pilar Lopez Pazmino.,...&Wendell A. Lim.(2021).T cell circuits that sense antigen density with an ultrasensitive threshold.Science.
MLA	Rogelio A. Hernandez-Lopez,et al."T cell circuits that sense antigen density with an ultrasensitive threshold".Science (2021).