CTLA-4 tail fusion enhances CAR-T antitumor immunity

被引:13
作者
Zhou, Xiaoyu [1 ,2 ,3 ]
Cao, Hanbing [1 ,2 ,3 ]
Fang, Shao-Yu [1 ,2 ,3 ]
Chow, Ryan D. [1 ,2 ,3 ,4 ,5 ,6 ]
Tang, Kaiyuan [1 ,2 ,3 ,4 ]
Majety, Medha [1 ,2 ,3 ,7 ]
Bai, Meizhu [1 ,2 ,3 ]
Dong, Matthew B. [1 ,2 ,3 ,5 ,6 ,8 ]
Renauer, Paul A. [1 ,2 ,3 ,4 ]
Shang, Xingbo [2 ,3 ,9 ]
Suzuki, Kazushi [1 ,2 ,3 ]
Levchenko, Andre [2 ,3 ,9 ]
Chen, Sidi [1 ,2 ,3 ,4 ,5 ,8 ,10 ,11 ,12 ]
机构
[1] Yale Univ, Dept Genet, Sch Med, New Haven, CT 06510 USA
[2] Yale Univ, Syst Biol Inst, West Haven, CT 06520 USA
[3] Yale Univ, Ctr Canc Syst Biol, West Haven, CT 06520 USA
[4] Yale Univ, Mol Cell Biol Genet & Dev Program, New Haven, CT 06520 USA
[5] Yale Univ, MD PhD Program, New Haven, CT 06520 USA
[6] Yale Univ, Dept Immunobiol, New Haven, CT USA
[7] Yale Coll, New Haven, CT USA
[8] Yale Univ, Immunobiol Program, New Haven, CT 06520 USA
[9] Yale Univ, Dept Biomed Engn, New Haven, CT USA
[10] Yale Univ, Comprehens Canc Ctr, Sch Med, New Haven, CT 06510 USA
[11] Yale Univ, Stem Cell Ctr, Sch Med, New Haven, CT 06510 USA
[12] Yale Univ, Ctr Biomed Data Sci, Sch Med, New Haven, CT 06510 USA
基金
美国国家卫生研究院;
关键词
4-1BB COSTIMULATION; GENE-EXPRESSION; CUTTING EDGE; CELLS; INTERNALIZATION; ENDOCYTOSIS; REGULATOR; TISSUE;
D O I
10.1038/s41590-023-01571-5
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Chimeric antigen receptor (CAR)-T cells are powerful therapeutics; however, their efficacy is often hindered by critical hurdles. Here utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail, we reprogram CAR function and substantially enhance CAR-T efficacy in vivo. CAR-T cells with monomeric, duplex or triplex CTLA-4 cytoplasmic tails (CCTs) fused to the C terminus of CAR exhibit a progressive increase in cytotoxicity under repeated stimulation, accompanied by reduced activation and production of proinflammatory cytokines. Further characterization reveals that CARs with increasing CCT fusion show a progressively lower surface expression, regulated by their constant endocytosis, recycling and degradation under steady state. The molecular dynamics of reengineered CAR with CCT fusion results in reduced CAR-mediated trogocytosis, loss of tumor antigen and improved CAR-T survival. CARs with either monomeric (CAR-1CCT) or duplex CCTs (CAR-2CCT) have superior antitumor efficacy in a relapsed leukemia model. Single-cell RNA sequencing and flow cytometry analysis reveal that CAR-2CCT cells retain a stronger central memory phenotype and exhibit increased persistence. These findings illuminate a unique strategy for engineering therapeutic T cells and improving CAR-T function through synthetic CCT fusion, which is orthogonal to other cell engineering techniques. Chimeric antigen receptor (CAR)-T cells may become exhausted, non-functional or deplete their target cells of antigen, limiting their efficacy. Chen and colleagues fuse the CTLA-4 cytoplasmic tail to a CAR, which compromises trogocytosis and increases the functional capacity of CAR-T cells.
引用
收藏
页码:1499 / 1510
页数:33
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