Meazza Raffaella, Falco Michela, Loiacono Fabrizio, Canevali Paolo, Della Chiesa Mariella, Bertaina Alice, Pagliara Daria, Merli Pietro, Indio Valentina, Galaverna Federica, Algeri Mattia, Moretta Francesca, Colomar-Carando Natalia, Muccio Letizia, Sivori Simona, Pession Andrea, Mingari Maria Cristina, Moretta Lorenzo, Moretta Alessandro, Locatelli Franco, Pende Daniela
Laboratory of Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Policlinico San Martino, 16132 Genoa, Italy.
Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
Cancers (Basel). 2020 Aug 5;12(8):2187. doi: 10.3390/cancers12082187.
NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIRNKG2ACD57 NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed.
自然杀伤细胞（NK细胞）在人类白细胞抗原（HLA）单倍体相合造血干细胞移植（haplo-HSCT）中可发挥显著的移植物抗白血病（GvL）效应。在此，我们剖析了80例小儿急性白血病患者的NK细胞库，这些患者先前报道在去除αβT/B细胞的haplo-HSCT后临床结局良好。这种移植物处理策略允许共同输注成熟免疫细胞，主要是NK细胞和γδT细胞，以及造血干细胞（HSC）。为促进基于NK细胞的抗白血病活性，80例患者中有36例接受了NK细胞同种异体反应性供体移植，根据移植物抗宿主方向的杀伤细胞免疫球蛋白样受体（KIR）/KIR配体错配来定义。对这些患者重建的NK细胞库分析显示，造血干细胞移植后1个月，成熟且有功能的KIR⁺NKG2A⁻CD57⁺NK细胞比例相对较高，包括同种异体反应性NK细胞亚群。因此，与移植物一起过继输注的NK细胞作为效应细胞的成熟来源持续存在，而新的NK细胞则从供体造血干细胞分化而来。值得注意的是，同种异体反应性NK细胞亚群具有最高的抗白血病活性，其在重建库中的大小可能受人类巨细胞病毒（HCMV）激活的影响。虽然供体NK细胞的表型模式对移植后HCMV激活没有影响，但在受者中，HCMV感染/激活促进了更分化的NK细胞表型。在该队列中，未观察到分化的NK细胞与无复发生存之间存在显著相关性。
