Reversal of T Cell Exhaustion by the First Donor Lymphocyte Infusion Is Associated with the Persistently Effective Antileukemic Responses in Patients with Relapsed AML after Allo-HSCT
Reversal of T Cell Exhaustion by the First Donor Lymphocyte Infusion Is Associated with the Persistently Effective Antileukemic Responses in Patients with Relapsed AML after Allo-HSCT
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首次供体淋巴细胞输注逆转 T 细胞耗竭与 Allo-HSCT 后复发性 AML 患者持续有效的抗白血病反应相关。
DOI：
10.1016/j.bbmt.2018.03.030
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发表时间：
2018-07-01
影响因子：
4.3
通讯作者：
Huang, Xiao-Jun
中科院分区：
文献类型：
--
作者：
Liu, Long;Chang, Ying-Jun;Huang, Xiao-Jun
供者淋巴细胞输注（DLI）是治疗异基因造血干细胞移植（allo-HSCT）后急性髓性白血病（AML）复发的有效方法，可显著提高复发患者的生存率。然而，AML复发患者DLI后有效抗白血病应答的机制仍不明确。在此，我们在41例首次AML复发患者和41例非复发AML对照受试者的前瞻性队列中研究了T细胞耗竭在allo-HSCT后AML复发中的作用，并通过使用流式细胞术检测T细胞的表型和功能来确定DLI是否通过逆转复发队列中的T细胞耗竭来发挥有效的抗白血病作用。我们发现，CD 4（+）和CD 8（+）T细胞都经历了耗竭，PD-1和Tim-3的共表达上调，细胞因子产生，增殖和细胞毒性潜力的功能障碍。首次DLI逆转T细胞耗竭与复发性AML患者的持续完全缓解相关。此外，骨髓中成功DLI后T细胞耗竭状态的逆转与CD 4/CD 8 T细胞比率的逆转减轻同时发生。总之，我们的研究表明，T细胞耗竭和AML复发allo-HSCT后的临床相关性，并揭示了逆转T细胞耗竭的DLI抗白血病反应的作用，并确定可能的免疫学标记物，以评估和预测DLI诱导的移植物抗白血病效应。(C)2018年美国血液和骨髓移植协会。
Donor lymphocyte infusion (DLI) is an effective approach to treat acute myelogenous leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) that significantly improves the survival of relapsed patients. However, the mechanism of an effective antileukemic response following DLI in AML relapse remains elusive. Here, we investigated the role of T cell exhaustion in AML relapse after allo-HSCT in prospective cohorts of 41 patients with the first AML relapse and 41 nonrelapsed AML control subjects after allo-HSCT and determined whether DLI exerts effective antileukemic effects by reversing T cell exhaustion in the relapsed cohorts by detecting the phenotypes and functions of T cells using flow cytometry. We found that both CD4(+ )and CD8(+)T cells experienced exhaustion with upregulated coexpression of PD-1 and Tim-3, and functional impairments in cytokine production, proliferation, and cytotoxic potentials. The reversal of T cell exhaustion by the first DLI is associated with persistent complete remission in relapsed AML patients. In addition, the reversal of T cell-exhausted status after successful DLI in bone marrow was concurrent with the mitigated inversion of CD4/CD8 T cell ratio. In conclusion, our study shows a clinical correlation between T cell exhaustion and AML relapse after allo-HSCT, and uncovers the role of reversing T cell exhaustion in the antileukemic response by DLI and identifies possible immunological markers to evaluate and predict the graftversus-leukemia effects induced by DLI. (C) 2018 American Society for Blood and Marrow Transplantation.