Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, North Carolina.
Immune Monitoring Core Laboratory, Levine Cancer Institute/Atrium Health, Charlotte, North Carolina.
Biol Blood Marrow Transplant. 2019 Mar;25(3):459-465. doi: 10.1016/j.bbmt.2018.11.015. Epub 2018 Nov 24.
Data indicate reversal of immune dysfunction with active treatment; however, the precise contribution of specific immune effector and immune suppressor components to achieve a minimal residual disease (MRD) state and immunomodulatory drug-mediated immunomodulatory effects in multiple myeloma (MM) patients remains poorly understood. In this prospective proof-of-principle study we sought to determine the dynamic alterations in natural killer (NK), NK-T, and T cells, including maturation and activating/inhibitory repertoire associated with MRD versus MRD status after autologous stem cell transplantation (ASCT) and during lenalidomide-based maintenance therapy. Of the 46MM patients enrolled, 36 had bone marrow MRD assessment 60+ days post-ASCT, 30 had longitudinal blood immunotyping during maintenance (pretherapy and after cycles 1, 3, and 6), and 20 had both MRD assessment and longitudinal immunotyping. Multicolor flow cytometry was used for MRD and immunotyping. Although the absolute number of NK cells was significantly lower in patients with MRD response, phenotypically NK cells in these patients displayed higher expression of activating receptors KIRDS4 and decreased expression of inhibitory molecules NKG2A compared with the MRD group. Furthermore, we observed significantly lower frequencies of T cells displaying KIR3DL1 in MRD versus MRD patients. Longitudinal immunotyping during lenalidomide maintenance showed loss of mature NK effector function, augmentation of NK-T effector function, and acquisition of PD1 independent anergic state. Our findings also suggest skewing of T cells toward an exhausted state during the maintenance phase in MRD patients. Put together, these observations provide a distinctive signature for MRD and MRD groups. These data support exploration of immune profiling in prospective clinical trials according to MRD-defined responses to identify patients that may benefit from maintenance intensification/modification or maintenance withdrawal.
数据表明，积极治疗可逆转免疫功能障碍；然而，特定的免疫效应和免疫抑制成分在多发性骨髓瘤（MM）患者中达到微小残留病（MRD）状态和免疫调节药物介导的免疫调节作用的确切贡献仍知之甚少。在这项前瞻性原理验证研究中，我们试图确定自然杀伤（NK）、NK-T 和 T 细胞的动态变化，包括与 ASCT 后和来那度胺为基础的维持治疗期间的 MRD 与 MRD 状态相关的成熟和激活/抑制谱。在纳入的 46 名 MM 患者中，36 名患者在 ASCT 后 60 天以上进行骨髓 MRD 评估，30 名患者在维持治疗期间进行纵向血液免疫分型（治疗前和周期 1、3 和 6 后），20 名患者同时进行 MRD 评估和纵向免疫分型。多色流式细胞术用于 MRD 和免疫分型。尽管有 MRD 反应的患者的 NK 细胞绝对数量明显较低，但这些患者的 NK 细胞表型显示出更高的激活受体 KIRDS4 的表达和抑制分子 NKG2A 的表达降低，与 MRD 组相比。此外，我们观察到在 MRD 患者中，表达 KIR3DL1 的 T 细胞频率明显较低。来那度胺维持期间的纵向免疫分型显示成熟 NK 效应功能丧失，NK-T 效应功能增强，以及获得 PD1 独立的无反应状态。我们的研究结果还表明，在 MRD 患者的维持阶段，T 细胞向衰竭状态倾斜。综上所述，这些观察结果为 MRD 和 MRD 组提供了独特的特征。这些数据支持根据 MRD 定义的反应在前瞻性临床试验中探索免疫谱，以确定可能受益于维持强化/修改或维持退出的患者。
