TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors
TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors
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通过 CRISPR 抑制 TGFβ 促进 CAR-T 细胞对抗实体瘤的长期功效
DOI：
10.1172/jci.insight.133977
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发表时间：
2020-02-27
期刊：
影响因子：
8
通讯作者：
Wang, Haoyi
中科院分区：
文献类型：
--
作者：
Tang, Na;Cheng, Chen;Wang, Haoyi
近年来，嵌合抗原受体修饰的T细胞（CAR T细胞）疗法已被证明是一种有前途的抗癌方法。尽管如此，这种方法在消除实体瘤方面仍然面临着多重挑战，其中之一是免疫抑制肿瘤微环境（TME）。在这里，我们证明了用CRISPR/Cas9技术敲除CAR T细胞中的内源性TGF-β受体II（TGFBR 2）可以减少诱导的Treg转化并防止CAR T细胞的耗尽。同时，TGFBR 2编辑的CAR T细胞在细胞系来源的异种移植物和患者来源的异种移植物实体瘤模型中均具有更好的体内肿瘤消除功效，无论是局部还是全身施用。此外，TGFBR 2编辑的CAR T细胞可以有效地消除小鼠中对侧再接种的异种移植物，其中中央记忆和效应记忆亚群的循环CAR T细胞内的记忆亚群的比例增加。总之，我们通过敲除内源性TGFBR 2大大改善了CAR T细胞在富含TGF-β的肿瘤环境中的体外和体内功能，并提出了一种潜在的新方法来改善CAR T细胞治疗实体瘤的疗效。
In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-beta receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line-derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-beta-rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors.