Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy
Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy
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DOI：
10.1038/s41586-019-1821-z
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发表时间：
2019-12-19
期刊：
影响因子：
64.8
通讯作者：
Chi, Hongbo
中科院分区：
文献类型：
--
作者：
Wei, Jun;Long, Lingyun;Chi, Hongbo
过继细胞治疗代表了癌症免疫治疗的一种新范式，但它可能受到转移的T细胞持久性和功能差的限制(1)。在这里，我们使用体内联合CRISPR-Cas9突变筛选方法来证明，通过靶向REGNASE-1，CD8(+)T细胞被重新编程为具有广泛积累、更好的持久性和强大的肿瘤效应功能的长寿效应细胞。REGNASE-1缺陷的CD8(+)T细胞对小鼠黑色素瘤和白血病模型的治疗效果显著改善。通过使用二级基因组规模的CRISPR-CAS9筛选，我们确定BATF是REGNASE-1的关键靶点，并且是塑造抗肿瘤反应的变阻器。BATF的丢失抑制了REGNASE-1缺陷的CD8(+)T细胞的积累和线粒体适合性的增加。相比之下，靶向其他信号因子-包括PTPN2和SOCS1-提高了REGNASE-1缺陷的CD8(+)T细胞的治疗效果。我们的研究结果表明，T细胞的持久性和效应器功能可以在肿瘤免疫中协调，并为提高肿瘤过继细胞治疗的疗效指明了途径。
Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells(1). Here we use an in vivo pooled CRISPR-Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8(+) T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours. REGNASE-1-deficient CD8(+) T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia. By using a secondary genome-scale CRISPR-Cas9 screening, we identify BATF as the key target of REGNASE-1 and as a rheostat that shapes antitumour responses. Loss of BATF suppresses the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8(+) T cells. By contrast, the targeting of additional signalling factors-including PTPN2 and SOCS1-improves the therapeutic efficacy of REGNASE-1-deficient CD8(+) T cells. Our findings suggest that T cell persistence and effector function can be coordinated in tumour immunity and point to avenues for improving the efficacy of adoptive cell therapy for cancer.