肿瘤细胞治疗研究
英文原题：IL-4 drives exhaustion of CD8(+) CART cells.
对CAR-T（CART）细胞疗法的持久反应仍然有限，部分原因是CART细胞耗竭。
对CAR-T（CART）细胞疗法的持久反应仍然有限，部分原因是CART细胞耗竭。在此，我们通过三种独立方法研究CART细胞耗竭的调控，包括：使用体外耗竭模型进行全基因组CRISPR敲除筛选，对基线和耗竭CART细胞进行RNA和ATAC测序，以及对ZUMA-1临床试验中应答者和无应答者的输注前CART细胞产品进行RNA和ATAC测序。每种方法都鉴定出白细胞介素（IL）-4是CART细胞功能障碍的调节因子。此外，经IL-4处理的CD8+ CART细胞独立于CD4+ CART细胞的存在而出现耗竭迹象。相反，IL-4通路编辑或CART细胞与IL-4单克隆抗体联合使用，在套细胞淋巴瘤异种移植小鼠模型中提高了抗肿瘤疗效并减少了CART细胞耗竭迹象。因此，我们既鉴定出IL-4在诱导CART耗竭中的作用，也鉴定出可转化用于改善CART细胞疗法的方法。
Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8 + CART cells develop signs of exhaustion independently of the presence of CD4 + CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.
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