Abstract：
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for a number of hemato-oncological disorders. In fact, allo-HSCT is considered as one of the most successful immunotherapies as its clinical efficacy is based on the donor T-cells\' capacity to control residual disease. This process is known as the graft-versus-leukemia (GvL) reaction. However, alloreactive T-cells can also recognize the host as foreign and trigger a systemic potentially life-threatening inflammatory disorder termed graft-versus-host disease (GvHD). A better understanding of the underlying mechanisms that lead to GvHD or disease relapse could help us to improve efficacy and safety of allo-HSCT. In recent years, extracellular vesicles (EVs) have emerged as critical components of intercellular crosstalk. Cancer-associated EVs that express the immune checkpoint molecule programmed death-ligand 1 (PD-L1) can suppress T-cell responses and thus contribute to immune escape. At the same time, it has been observed that inflammation triggers PD-L1 expression as part of a negative feedback network.Here, we investigated whether circulating EVs following allo-HSCT express PD-L1 and tested their efficacy to suppress the ability of (autologous) T-cells to effectively target AML blasts. Finally, we assessed the link between PD-L1 levels on EVs to (T-)cell reconstitution, GvHD, and disease relapse.We were able to detect PD-L1+ EVs that reached a peak PD-L1 expression at 6 weeks post allo-HSCT. Development of acute GvHD was linked to the emergence of PD-L1high EVs following allo-HSCT. Moreover, PD-L1 levels correlated positively with GvHD grade and declined (only) on successful therapeutic intervention. T-cell-inhibitory capacity was higher in PD-L1high EVs as compared with their PD-L1low counterparts and could be antagonized using PD-L1/PD-1 blocking antibodies. Abundance of T-cell-suppressive PD-L1high EVs appears to also impact GvL efficacy as patients were at higher risk for relapse. Finally, patients of PD-L1high cohort displayed a reduced overall survival.Taken together, we show that PD-L1-expressing EVs are present following allo-HSCT. PD-L1 levels on EVs correlate with their ability to suppress T-cells and the occurrence of GvHD. The latter observation may indicate a negative feedback mechanism to control inflammatory (GvHD) activity. This intrinsic immunosuppression could subsequently promote disease relapse.
摘要：
异基因造血干细胞移植（allo-HSCT）代表了许多血液肿瘤疾病的唯一治愈性治疗选择。事实上,allo-HSCT被认为是最成功的免疫疗法之一,因为其临床疗效基于供体T细胞控制残留疾病的能力。该过程称为移植物抗白血病(GvL)反应。然而,同种反应性T细胞也可将宿主识别为外来物,并引发全身性潜在危及生命的炎症性疾病,称为移植物抗宿主病(GvHD).更好地了解导致GvHD或疾病复发的潜在机制可以帮助我们提高allo-HSCT的疗效和安全性。近年来,细胞外囊泡（EV）已成为细胞间串扰的关键组成部分。表达免疫检查点分子程序性死亡配体1（PD-L1）的癌症相关EV可以抑制T细胞反应，从而有助于免疫逃逸。同时,已经观察到,作为负反馈网络的一部分,炎症会触发PD-L1表达.这里,我们调查了allo-HSCT后循环EV是否表达PD-L1,并测试了其抑制(自体)T细胞有效靶向AML母细胞的能力的功效.最后,我们评估了EV上PD-L1水平与（T-）细胞重建之间的联系，GvHD,和疾病复发。我们能够检测到在allo-HSCT后6周达到峰值PD-L1表达的PD-L1+EV。急性GvHD的发展与allo-HSCT后PD-L1高EV的出现有关。此外，PD-L1水平与GvHD等级呈正相关，并且（仅）在成功的治疗干预后下降。与PD-L1低对应体相比，PD-L1高EV的T细胞抑制能力更高，并且可以使用PD-L1/PD-1阻断抗体拮抗。T细胞抑制性PD-L1高EV的丰度似乎也影响GvL疗效，因为患者复发的风险较高。最后,PD-L1高队列患者的总生存率降低.一起来看,我们显示，在allo-HSCT后存在表达PD-L1的EV。EV上的PD-L1水平与其抑制T细胞的能力和GvHD的发生相关。后一种观察可能表明负反馈机制来控制炎症(GvHD)活性。这种内在的免疫抑制可以随后促进疾病复发。
