Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients
Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients
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DOI：
10.1038/s41375-020-0793-1
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发表时间：
2020-03-13
期刊：
影响因子：
11.4
通讯作者：
Feuchtinger, Tobias
中科院分区：
文献类型：
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作者：
Blaeschke, Franziska;Willier, Semjon;Feuchtinger, Tobias
恶性肿瘤与组织特异性免疫细胞的相互作用已经引起了人们对新兴免疫疗法的预后和干预的兴趣。我们分析了骨髓T细胞（bmT）作为肿瘤浸润淋巴细胞在小儿急性B细胞淋巴细胞白血病（ALL）。基于100例患者的数据，我们发现ALL与晚期CD 4（+）表型和早期CD 8（+）T细胞丢失相关。多因素分析证实，CD 4（+）bmT上的抑制性耗竭标志物TIM-3增加复发风险（RFS = 94.6/70.3%）。TIM-3表达的风险比几乎达到MRD的风险比（7.1 vs. 8.0），表明初次诊断时具有高频率TIM-3（+）CD 4（+）骨髓T细胞的患者发生ALL复发的风险增加7.1倍。野生型原代T细胞与CRISPR/Cas9介导的TIM-3敲除和TIM-3过表达的比较证实了TIM-3对针对ALL的T细胞应答的负面影响。TIM-3（+）CD 4（+）bmT在过表达CD 200的ALL中增加，导致抗白血病T细胞应答功能障碍。总之，TIM-3介导的bmT和白血病细胞之间的相互作用是儿童B系ALL复发的一个强风险因素。CD 200/TIM-3信号传导，而不是PD-1/PD-L1，被发现是ALL中T细胞功能障碍的机制，对未来的免疫治疗具有重要意义。
Interaction of malignancies with tissue-specific immune cells has gained interest for prognosis and intervention of emerging immunotherapies. We analyzed bone marrow T cells (bmT) as tumor-infiltrating lymphocytes in pediatric precursor-B cell acute lymphoblastic leukemia (ALL). Based on data from 100 patients, we show that ALL is associated with late-stage CD4(+) phenotype and loss of early CD8(+) T cells. The inhibitory exhaustion marker TIM-3 on CD4(+) bmT increased relapse risk (RFS = 94.6/70.3%) confirmed by multivariate analysis. The hazard ratio of TIM-3 expression nearly reached the hazard ratio of MRD (7.1 vs. 8.0) indicating that patients with a high frequency of TIM-3(+)CD4(+) bone marrow T cells at initial diagnosis have a 7.1-fold increased risk to develop ALL relapse. Comparison of wild type primary T cells to CRISPR/Cas9-mediated TIM-3 knockout and TIM-3 overexpression confirmed the negative effect of TIM-3 on T cell responses against ALL. TIM-3(+)CD4(+) bmT are increased in ALL overexpressing CD200, that leads to dysfunctional antileukemic T cell responses. In conclusion, TIM-3-mediated interaction between bmT and leukemia cells is shown as a strong risk factor for relapse in pediatric B-lineage ALL. CD200/TIM-3-signaling, rather than PD-1/PD-L1, is uncovered as a mechanism of T cell dysfunction in ALL with major implication for future immunotherapies.