Reina-Ortiz Chantal, Constantinides Michael, Fayd-Herbe-de-Maudave Alexis, Présumey Jessy, Hernandez Javier, Cartron Guillaume, Giraldos David, Díez Rosana, Izquierdo Isabel, Azaceta Gemma, Palomera Luis, Marzo Isabel, Naval Javier, Anel Alberto, Villalba Martín
Apoptosis, Immunity & Cancer Group, Dept. Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), Zaragoza, Spain.
CHU Montpellier, IRMB, Montpellier, France.
Oncoimmunology. 2020 Dec 29;10(1):1853314. doi: 10.1080/2162402X.2020.1853314.
In this study we evaluated the potential of expanded NK cells (eNKs) from two sources combined with the mAbs daratumumab and pembrolizumab to target primary multiple myeloma (MM) cells . In order to ascertain the best source of NK cells, we expanded and activated NK cells from peripheral blood (PB) of healthy adult donors and from umbilical cord blood (UCB). The resulting expanded NK (eNK) cells express CD16, necessary for carrying out antibody-dependent cellular cytotoxicity (ADCC). Cytotoxicity assays were performed on bone marrow aspirates of 18 MM patients and 4 patients with monoclonal gammopathy of undetermined significance (MGUS). Expression levels of PD-1 on eNKs and PD-L1 on MM and MGUS cells were also quantified. Results indicate that most eNKs obtained using our expansion protocol express a low percentage of PD-1 cells. UCB eNKs were highly cytotoxic against MM cells and addition of daratumumab or pembrolizumab did not further increase their cytotoxicity. PB eNKs, while effective against MM cells, were significantly more cytotoxic when combined with daratumumab. In a minority of cases, eNK cells showed a detectable population of PD1 cells. This correlated with low cytotoxic activity, particularly in UCB eNKs. Addition of pembrolizumab did not restore their activity. Results indicate that UCB eNKs are to be preferentially used against MM in the absence of daratumumab while PB eNKs have significant cytotoxic advantage when combined with this mAb.
在本研究中，我们评估了来自两种来源的扩增自然杀伤细胞（eNKs）与单克隆抗体达雷妥尤单抗和帕博利珠单抗联合用于靶向原发性多发性骨髓瘤（MM）细胞的潜力。为了确定自然杀伤细胞的最佳来源，我们从健康成年供者的外周血（PB）和脐带血（UCB）中扩增并激活了自然杀伤细胞。产生的扩增自然杀伤（eNK）细胞表达进行抗体依赖性细胞毒性（ADCC）所必需的CD16。对18例MM患者和4例意义未明的单克隆丙种球蛋白病（MGUS）患者的骨髓抽吸物进行了细胞毒性测定。还对eNKs上的PD-1和MM及MGUS细胞上的PD-L1表达水平进行了定量。结果表明，使用我们的扩增方案获得的大多数eNKs表达低百分比的PD-1细胞。UCB来源的eNKs对MM细胞具有高度细胞毒性，添加达雷妥尤单抗或帕博利珠单抗并未进一步增加其细胞毒性。PB来源的eNKs虽然对MM细胞有效，但与达雷妥尤单抗联合时细胞毒性显著增强。在少数情况下，eNK细胞显示出可检测到的PD1细胞群体。这与低细胞毒性活性相关，尤其是在UCB来源的eNKs中。添加帕博利珠单抗并未恢复其活性。结果表明，在没有达雷妥尤单抗的情况下，UCB来源的eNKs应优先用于对抗MM，而PB来源的eNKs与该单克隆抗体联合时具有显著的细胞毒性优势。
