DataSheet_1_Infusion of Host-Derived Unlicensed NK Cells Improves Donor Engraftment in Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation.pdf

Allogeneic hematopoietic cell transplantation (allo-HCT) is an efficacious and frequently the only treatment option for some hematological malignances. However, it often faces severe morbidities and/or mortalities due to graft versus host disease, and the severity of the conditioning regiment needed, that result in toxicity-related issues poorly tolerable for some patients. These shortcomings have led to the development of less aggressive alternatives like non-myeloablative (NMAC) or reduced-intensity conditioning regiments (RIC). However, these approaches tend to have an increase of cancer relapse and limited persistence of donor-specific chimerism. Thus, strategies that lead towards an accelerated and more durable donor engraftment are still needed. Here, we took advantage of the ability of host-derived unlicensed NK (UnLicNK) cells to favor donor cell engraftment during myeloablative allo-HCT, and evaluated if the adoptive transfer of this cell type can improve donor chimerism in NAMC settings. Indeed, the infusion of these cells significantly increased mixed chimerism in a sublethal allo-HCT mouse model, resulting in a more sustainable donor cell engraftment when compared to the administration of licensed NK cells or HCT controls. We observed an overall increase in the total number and proportion of donor B, NK and myeloid cells after UnLicNK cell infusion. Additionally, the extension and durability of donor chimerism was similar to the one obtained after the tolerogenic Tregs infusion. These results serve as the needed bases for the implementation of the adoptive transfer of UnLicNK cells to upgrade NMAC protocols and enhance allogeneic engraftment during HCT.

异基因造血细胞移植（allogeneic hematopoietic cell transplantation, allo-HCT）是部分血液系统恶性肿瘤的有效治疗手段，且往往是此类疾病唯一可选的治疗方案。然而，该疗法常因移植物抗宿主病（graft versus host disease, GVHD）以及所需高强度预处理方案带来的严重不良反应，导致部分患者难以耐受相关毒性相关并发症，进而引发较高的发病率与死亡率。上述局限推动了低强度替代方案的开发，例如非清髓性预处理（non-myeloablative, NMAC）或减低剂量预处理（reduced-intensity conditioning regiments, RIC）方案。但此类策略往往伴随癌症复发风险升高以及供者特异性嵌合持久性不足的问题。因此，目前仍亟需能够实现供体细胞快速且持久植入的干预策略。本研究借助宿主来源未授权NK（unlicensed NK, UnLicNK）细胞在清髓性异基因造血细胞移植中可促进供体细胞植入的特性，探索了此类细胞的过继转移是否可改善非清髓性预处理方案下的供者嵌合状态。实验结果显示，在亚致死剂量异基因造血细胞移植小鼠模型中，输注未授权NK细胞可显著提升混合嵌合比例，相较于输注已授权NK细胞（licensed NK cells）或单纯造血细胞移植对照组，其供体细胞植入的可持续性更为优异。研究还观察到，未授权NK细胞输注后，供体来源B细胞、NK细胞及髓系细胞的总数与占比均整体升高。此外，供体嵌合的维持时长与持久性，与耐受性调节性T细胞（tolerogenic Tregs）输注后获得的效果相当。本研究结果为实施未授权NK细胞过继转移以优化非清髓性预处理方案、提升造血细胞移植过程中的异基因植入效率提供了必要的理论基础。