Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital & Peking University Institute of Hematology, Beijing, China.
Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital & Peking University Institute of Hematology, Beijing, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
Biol Blood Marrow Transplant. 2018 Jul;24(7):1350-1359. doi: 10.1016/j.bbmt.2018.03.030. Epub 2018 Apr 9.
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 graft-versus-leukemia effects induced by DLI.
供者淋巴细胞输注（DLI）是治疗异基因造血干细胞移植（allo-HSCT）后急性髓系白血病（AML）复发的有效方法，可显著改善复发患者的生存。然而，DLI 后在 AML 复发中产生有效抗白血病反应的机制仍不清楚。在这里，我们通过流式细胞术检测 T 细胞表型和功能，在 41 例首次 AML 复发和 41 例 allo-HSCT 后非复发 AML 对照患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抗白血病作用。我们发现 CD4 和 CD8 T 细胞均经历了衰竭，表现为 PD-1 和 Tim-3 的共表达上调，以及细胞因子产生、增殖和细胞毒性潜力的功能障碍。首次 DLI 逆转 T 细胞衰竭与复发 AML 患者持续完全缓解相关。此外，在骨髓中成功进行 DLI 后，T 细胞耗竭状态的逆转与 CD4/CD8 T 细胞比值的减轻反转同时发生。总之，我们的研究显示了 T 细胞耗竭与 allo-HSCT 后 AML 复发之间的临床相关性，并揭示了 DLI 逆转 T 细胞耗竭在抗白血病反应中的作用，并确定了可能的免疫标志物来评估和预测 DLI 诱导的移植物抗白血病效应。
