肿瘤细胞治疗研究
英文原题：CCR4 expression defines a targetable subset of T-cell acute lymphoblastic leukemia.
我们分析了AALL0434临床试验中40例接受治疗的T-ALL患者的微环境，并鉴定出一个富集于骨髓的CCR4+ FOXP3+ T调节细胞亚群，该亚群表达免疫检查点（PD-1和TIGIT），并可通过抗CCR4治疗进行靶向。
复发/难治性T细胞急性淋巴细胞白血病（T-ALL）患者预后极差，这在很大程度上是由于对化疗的反应不能持续以及靶向治疗选择有限所致。T-ALL中的表面抗原靶点包括CD2、CD5、CD7和CD38；然而，这些靶点的持续临床开发受到以下因素的挑战：（1）生产过程中的T细胞自相残杀，（2）治疗期间的T细胞耗竭，以及（3）靶点阴性复发的高频率。在此，我们结合流式细胞术、单细胞基因组学和bulk RNA测序，确定CC趋化因子受体4型（CCR4）是T-ALL中的一个新型表面靶点。我们分析了来自AALL0434临床试验中40例接受治疗患者的T-ALL微环境，并鉴定出一个富集于骨髓的CCR4+ FOXP3+ T调节细胞亚群，该亚群表达免疫检查点（PD-1和TIGIT），并可用抗CCR4治疗进行靶向。最后，我们描述了抗CCR4CAR-T 细胞疗法在体外和体内模型中的临床前疗效，为化疗难治性T-ALL的未来转化研究铺平了道路。
Patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) have a dismal prognosis largely mediated by nonsustained responses to chemotherapy and few targeted therapy options. Surface antigen targets in T-ALL include CD2, CD5, CD7, and CD38; however, ongoing clinical development of these targets is challenged by (1) T-cell fratricide during manufacturing, (2) T-cell depletion during treatment, and (3) high frequency of target-negative relapse. Here, we use a combination of flow cytometry, single-cell genomics, and bulk RNA sequencing to identify CC chemokine receptor type 4 (CCR4) as a novel surface target in T-ALL. We analyzed the T-ALL microenvironment from 40 patients treated on the AALL0434 clinical trial and identified a subpopulation of bone marrow-enriched CCR4+ FOXP3+ T-regulatory cells that express immune checkpoints (PD-1 and TIGIT) and could be targeted with anti-CCR4 therapy. Finally, we describe the preclinical efficacy of an anti-CCR4 chimeric antigen receptor T-cell therapy in in vitro and in vivo models, paving the way for future translational efforts in chemotherapy-refractory T-ALL.
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