State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Transplant Cell Ther. 2022 Sep;28(9):589.e1-589.e10. doi: 10.1016/j.jtct.2022.06.007. Epub 2022 Jun 14.
Natural killer (NK) cells are the first lymphocyte population to recover after allogenic hematopoietic stem cell transplantation (allo-HSCT) and mediate potent graft versus leukemia effect, particularly in the settings of T-cell depletion. However, the significance of NK cells after unmanipulated transplantation is less clear, and factors affecting early NK reconstitution remain elusive. We retrospectively analyze 180 patients with acute myeloid leukemia or myelodysplastic syndrome who received unmanipulated allografts. We focus on the early NK reconstitution and its association with disease relapse, overall survival, and cytomegalovirus (CMV) reactivation. We also analyze factors that affect NK recovery, such as dose of CD34 cells in the graft and T-cell recovery after transplantation. Penalized splines and receiver operator characteristic curves demonstrate a strong association between blood NK counts at 30 days after allo-HSCT (NK30) and all-cause mortality, with the cutoff value being close to the median value that divides patients dichotomously. Subsequent analysis shows that rapid NK recovery (higher NK30 or higher NK60) is associated with reduced disease relapse and better survival. Robust NK recovery (NK30 and NK60) also correlates with lower incidence of CMV reactivation. We find that NK30 is associated with the numbers of CD34 cells (r = 0.739, P < .001) but not mature NK cells contained in the graft. In a small subset (N = 12) of the cohort, patients in continuous complete remission (N = 6) demonstrate higher frequencies of CD34CD7 progenitor cells and CD56 NK cells in the day 30 bone marrow as compared to patients with disease relapse within 1 year (N = 6). Furthermore, neither T-cell recovery after transplantation nor application of anti-thymocyte globulins (ATG) in the conditioning regimen demonstrate suppressive effect on NK recovery. Rapid NK cell recovery is associated with improved prognosis of unmanipulated transplantation for myeloid malignancies. Manipulation of NK cell recovery represents a feasible approach to improve transplant outcomes for example by optimizing CD34 cells in the graft.
自然杀伤 (NK) 细胞是异基因造血干细胞移植 (allo-HSCT) 后第一个恢复的淋巴细胞群，可介导强大的移植物抗白血病效应，尤其是在 T 细胞耗竭的情况下。然而，未处理移植后 NK 细胞的意义尚不清楚，影响早期 NK 重建的因素仍不清楚。我们回顾性分析了 180 例接受未处理同种异体移植的急性髓系白血病或骨髓增生异常综合征患者。我们专注于早期 NK 重建及其与疾病复发、总生存和巨细胞病毒 (CMV) 再激活的关系。我们还分析了影响 NK 恢复的因素，例如移植物中 CD34 细胞的剂量和移植后 T 细胞的恢复。惩罚样条和接收者操作特征曲线表明，allo-HSCT 后 30 天的血液 NK 计数 (NK30) 与全因死亡率之间存在很强的关联，截止值接近将患者分为两组的中位数。后续分析表明，快速 NK 恢复（更高的 NK30 或更高的 NK60）与降低疾病复发和改善生存相关。强大的 NK 恢复（NK30 和 NK60）也与 CMV 再激活的发生率较低相关。我们发现 NK30 与移植物中包含的 CD34 细胞数量相关（r=0.739，P<0.001），但与成熟 NK 细胞无关。在队列的一小部分（N=12）中，与 1 年内疾病复发的患者（N=6）相比，持续完全缓解的患者（N=6）在第 30 天骨髓中具有更高频率的 CD34CD7 祖细胞和 CD56 NK 细胞。此外，移植后 T 细胞的恢复或在预处理方案中使用抗胸腺细胞球蛋白 (ATG) 均未显示对 NK 恢复有抑制作用。快速 NK 细胞恢复与未处理移植治疗髓系恶性肿瘤的预后改善相关。NK 细胞恢复的操作代表了一种可行的方法，可以通过优化移植物中的 CD34 细胞来改善移植结果。
