Journal
IMMUNITY
Volume 53, Issue 2, Pages 456-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2020.07.011
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Funding
- National Key R&D Program of China, China [2019YFA0111000]
- National Natural Science Foundation of China, China [31670919, 31530022, 31861133009, 31621003]
- Science and Technology Commission of Shanghai Municipality of China, China [17411962000]
- Health and Family Planning Commission of Shanghai Municipality of China, China [2019SY059]
- Fountain-Valley Life Sciences Fund from Chinese Academy of Sciences, China
- [XDB29000000]
- [QYZDB-SSW-SMC048]
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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.
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