美国圣裘德儿童研究医院的迟洪波团队发现，靶向REGNASE-1可重编程长效效应T细胞从而用于肿瘤治疗。2019年12月11日，《自然》杂志在线发表了这一论文。

研究人员使用一种体内CRISPR-Cas9库诱变筛选方法证明，通过靶向REGNASE-1，CD8阳性T细胞可以重编程为长效效应细胞，并在肿瘤中具有广泛的积累、更好的持久性和强大的效应功能。缺乏REGNASE-1的CD8阳性T细胞对黑色素瘤和白血病小鼠模型的治疗效果显著提高。

通过使用二级基因组规模的CRISPR–Cas9筛选，研究人员将BATF确定为REGNASE-1的主要靶标，并将其定为塑造抗肿瘤反应的因子。BATF的丢失抑制了REGNASE-1缺失的CD8阳性T细胞积累的增加和线粒体适应性。相比之下，靶向其他信号因子（包括PTPN2和SOCS1）可提高REGNASE-1缺陷型CD8阳性T细胞的治疗效果。

这些研究结果表明，T细胞的持久性和效应子功能可以在肿瘤免疫中得到协调，并为提高过继性细胞疗法治疗癌症的疗效指明了途径。

据介绍，过继性细胞疗法代表了癌症免疫疗法的新模式，但它可能由于转移T细胞的持久性和功能差而受到限制。

附：英文原文

Title: Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy

Author: Jun Wei, Lingyun Long, Wenting Zheng, Yogesh Dhungana, Seon Ah Lim, Cliff Guy, Yanyan Wang, Yong-Dong Wang, Chenxi Qian, Beisi Xu, Anil KC, Jordy Saravia, Hongling Huang, Jiyang Yu, John G. Doench, Terrence L. Geiger, Hongbo Chi

Issue&Volume: 2019-12-11

Abstract: Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells1. 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.

DOI: 10.1038/s41586-019-1821-z

Source: https://www.nature.com/articles/s41586-019-1821-z