A logic to cell-cell recognition There has been exciting progress in the field of cancer immunotherapy, which harnesses a patient's own immune system to kill cancer cells. However, achieving precise recognition of cancer cells remains challenging. Cells engineered with synthetic Notch (synNotch) receptors bind to specific antigens, and binding induces the expression of defined genes. Williams et al. used synNotch modules as transcriptional connectors that daisy-chain together multiple receptors. They engineered T cells that can recognize up to three target antigens expressed on or inside cancer cells and integrated these inputs to achieve NOT, AND, and OR logic. The engineered cells achieved precise recognition of targeted cancer cells. Science, this issue p. 1099 Linking multiple molecular recognition events via intracellular regulation provides a powerful way to engineer cellular-level recognition. Living cells often identify their correct partner or target cells by integrating information from multiple receptors, achieving levels of recognition that are difficult to obtain with individual molecular interactions. In this study, we engineered a diverse library of multireceptor cell-cell recognition circuits by using synthetic Notch receptors to transcriptionally interconnect multiple molecular recognition events. These synthetic circuits allow engineered T cells to integrate extra- and intracellular antigen recognition, are robust to heterogeneity, and achieve precise recognition by integrating up to three different antigens with positive or negative logic. A three-antigen AND gate composed of three sequentially linked receptors shows selectivity in vivo, clearing three-antigen tumors while ignoring related two-antigen tumors. Daisy-chaining multiple molecular recognition events together in synthetic circuits provides a powerful way to engineer cellular-level recognition.

中文翻译：

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通过转录连接多个受体设计的精确 T 细胞识别程序


细胞间识别的逻辑癌症免疫疗法领域取得了令人兴奋的进展，该疗法利用患者自身的免疫系统来杀死癌细胞。然而，实现对癌细胞的精确识别仍然具有挑战性。用合成 Notch (synNotch) 受体改造的细胞与特定抗原结合，结合诱导特定基因的表达。威廉姆斯等人。使用 synNotch 模块作为转录连接器，将多个受体以菊花链方式连接在一起。他们设计了能够识别癌细胞表面或内部表达的多达三种目标抗原的 T 细胞，并整合这些输入以实现“非”、“与”和“或”逻辑。工程细胞实现了对目标癌细胞的精确识别。科学，本期第 14 页。 1099 通过细胞内调节连接多个分子识别事件提供了一种设计细胞水平识别的强大方法。活细胞通常通过整合来自多个受体的信息来识别其正确的伴侣或靶细胞，从而达到通过个体分子相互作用难以获得的识别水平。在这项研究中，我们通过使用合成的 Notch 受体在转录上互连多个分子识别事件，设计了一个多样化的多受体细胞识别电路库。这些合成电路允许工程化 T 细胞整合细胞外和细胞内抗原识别，对异质性具有鲁棒性，并通过整合多达三种不同的正逻辑或负逻辑抗原来实现精确识别。由三个顺序连接的受体组成的三抗原与门在体内表现出选择性，清除三抗原肿瘤，同时忽略相关的二抗原肿瘤。 在合成电路中以菊花链方式将多个分子识别事件连接在一起，提供了一种设计细胞级识别的强大方法。