上海科技大学王皞鹏等研究人员合作发现，将嵌合抗原受体重设计可防止其泛素化和下调，从而表现出持久的抗肿瘤功效。该项研究成果于2020年8月5日在线发表在《免疫》杂志上。

Title: Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy

Author: Wentao Li, Shizhen Qiu, Jian Chen, Shutan Jiang, Wendong Chen, Jingwei Jiang, Fei Wang, Wen Si, Yilai Shu, Ping Wei, Gaofeng Fan, Ruijun Tian, Haitao Wu, Chenqi Xu, Haopeng Wang

Issue&Volume: 2020-08-05

Abstract: Clinical evidence suggests that poor persistence of chimeric antigen receptor-T cells(CAR-T) in patients limits therapeutic efficacy. Here, we designed a CAR with recyclablecapability to promote in vivo persistence and to sustain antitumor activity. We showed that the engagement of tumorantigens induced rapid ubiquitination of CARs, causing CAR downmodulation followedby lysosomal degradation. Blocking CAR ubiquitination by mutating all lysines in theCAR cytoplasmic domain (CARKR) markedly repressed CAR downmodulation by inhibiting lysosomal degradation whileenhancing recycling of internalized CARs back to the cell surface. Upon encounteringtumor antigens, CARKR-T cells ameliorated the loss of surface CARs, which promoted their long-term killingcapacity. Moreover, CARKR-T cells containing 4-1BB signaling domains displayed elevated endosomal 4-1BB signalingthat enhanced oxidative phosphorylation and promoted memory T cell differentiation,leading to superior persistence in vivo. Collectively, our study provides a straightforward strategy to optimize CAR-T antitumorefficacy by redirecting CAR trafficking.

DOI: 10.1016/j.immuni.2020.07.011

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30318-6