肿瘤细胞治疗研究
英文原题：IDR-induced CAR condensation improves the cytotoxicity of CAR-Ts against low-antigen cancers.
基于嵌合抗原受体（CAR）T 细胞的疗法在治疗其他方法难以治愈的癌症、尤其是 B 细胞恶性肿瘤方面显示出显著疗效。
嵌合抗原受体（CAR）T细胞疗法对难治性癌症、尤其是B细胞恶性肿瘤显示出显著疗效。然而，目前获美国食品药品监督管理局批准的CAR-T产品对低抗原表达的癌症敏感性不足，限制了其靶向能力。为提高CAR-T抗原敏感性，研究人员在靶向CD19、CD22和HER2的CAR中加入可促进信号凝聚的内在无序区域（IDR）。IDR CAR在CAR-T免疫突触中增强膜近端信号，进而增加细胞毒性因子释放，提高体外对低抗原表达癌细胞的杀伤能力，并改善体内抗肿瘤疗效。IDR CAR-T未观察到增强的组成性基础信号。综上，本研究证明IDR是一种增强CAR-T细胞毒性的新工具，并有望将CAR-T应用拓展至低抗原表达癌症。
Chimeric antigen receptor (CAR)-T cell-based therapies demonstrate remarkable efficacy for the treatment of otherwise intractable cancers, particularly B-cell malignancies. However, existing FDA-approved CAR-Ts are limited by low antigen sensitivity, rendering their insufficient targeting to low antigen-expressing cancers. To improve the antigen sensitivity of CAR-Ts, we engineered CARs targeting CD19, CD22, and HER2 by including intrinsically disordered regions (IDRs) that promote signaling condensation. The "IDR CARs" triggered enhanced membrane-proximal signaling in the CAR-T synapse, which led to an increased release of cytotoxic factors, a higher killing activity towards low antigen-expressing cancer cells in vitro, and an improved anti-tumor efficacy in vivo. No elevated tonic signaling was observed in IDR CAR-Ts. Together, we demonstrated IDRs as a new tool set to enhance CAR-T cytotoxicity and to broaden CAR-T's application to low antigen-expressing cancers.
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