Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy
Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy
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旨在防止泛素化和下调的嵌合抗原受体显示出持久的抗肿瘤功效
DOI：
10.1016/j.immuni.2020.07.011
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发表时间：
2020-08-18
期刊：
影响因子：
32.4
通讯作者：
Wang, Haopeng
中科院分区：
文献类型：
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作者：
Li, Wentao;Qiu, Shizhen;Wang, Haopeng
临床证据表明，嵌合抗原受体-T细胞（CAR-T）在患者体内的持久性差限制了治疗效果。在这里，我们设计了一种具有可回收能力的CAR，以促进体内持久性并维持抗肿瘤活性。我们发现，肿瘤抗原的参与诱导汽车的快速泛素化，导致CAR下调，随后是溶酶体降解。通过突变CAR胞质结构域（CAR（KR））中的所有赖氨酸来阻断CAR遍在化，通过抑制溶酶体降解同时增强内化汽车返回细胞表面的再循环，显着抑制CAR下调。在遇到肿瘤抗原时，CAR（KR）-T细胞改善了表面汽车的损失，这促进了它们的长期杀伤能力。此外，含有4-1BB信号传导结构域的CAR（KR）-T细胞显示升高的内体4-1BB信号传导，其增强氧化磷酸化并促进记忆T细胞分化，导致体内上级持久性。总的来说，我们的研究提供了一种直接的策略，通过重定向CAR运输来优化CAR-T的抗肿瘤功效。
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 recyclable capability to promote in vivo persistence and to sustain antitumor activity. We showed that the engagement of tumor antigens induced rapid ubiquitination of CARs, causing CAR downmodulation followed by lysosomal degradation. Blocking CAR ubiquitination by mutating all lysines in the CAR cytoplasmic domain (CAR(KR)) markedly repressed CAR downmodulation by inhibiting lysosomal degradation while enhancing recycling of internalized CARs back to the cell surface. Upon encountering tumor antigens, CAR(KR)-T cells ameliorated the loss of surface CARs, which promoted their long-term killing capacity. Moreover, CAR(KR)-T cells containing 4-1BB signaling domains displayed elevated endosomal 4-1BB signaling that 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 antitumor efficacy by redirecting CAR trafficking.