嵌合抗原受体（CAR）T细胞对具有免疫抑制微环境的实体瘤是无效的。为了克服抑制，研究人员设计了肿瘤特异性synNotch受体来局部诱导产生细胞因子IL-2的回路。这些回路有效地增强了CAR T细胞的浸润和免疫排斥肿瘤的清除，而没有全身性的毒性。最有效的IL-2诱导回路以自分泌和T细胞受体（TCR）或CAR非依赖的方式发挥作用，绕过了包括IL-2消耗或TCR信号抑制的抑制机制。
这些工程细胞在目标肿瘤中建立了一个立足点，合成Notch诱导的IL-2的产生使CAR介导的T细胞扩张和细胞杀伤得以启动。因此，有可能重建合成T细胞回路，激活抗肿瘤反应最终所需的输出，但其方式是回避肿瘤抑制的关键点。
附：英文原文
Title: Synthetic cytokine circuits that drive T cells into immune-excluded tumors
Author: Greg M. Allen, Nicholas W. Frankel, Nishith R. Reddy, Hersh K. Bhargava, Maia A. Yoshida, Sierra R. Stark, Megan Purl, Jungmin Lee, Jacqueline L. Yee, Wei Yu, Aileen W. Li, K. Christopher Garcia, Hana El-Samad, Kole T. Roybal, Matthew H. Spitzer, Wendell A. Lim
Issue&Volume: 2022-12-16
Abstract: Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch–induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.
DOI: aba1624
Source: https://www.science.org/doi/10.1126/science.aba1624