Benyamine Audrey, Le Roy Aude, Mamessier Emilie, Gertner-Dardenne Julie, Castanier Céline, Orlanducci Florence, Pouyet Laurent, Goubard Armelle, Collette Yves, Vey Norbert, Scotet Emmanuel, Castellano Remy, Olive Daniel
Inserm, U1068, Centre de Recherche en Cancérologie de Marseille (CRCM), Immunity & Cancer, Institut Paoli-Calmettes, Aix-Marseille Université UM 105 , CNRS UMR 7258 , Marseilles, France.
Inserm, U1068, Centre de Recherche en Cancérologie de Marseille (CRCM), molecular Oncology, Institut Paoli-Calmettes, Aix-Marseille Université UM 105 , CNRS UMR 7258 , Marseilles, France.
Oncoimmunology. 2016 Apr 25;5(10):e1146843. doi: 10.1080/2162402X.2016.1146843. eCollection 2016.
Given their recognized ability to kill acute myeloid leukemia (AML) blasts both and , Vγ9Vδ2 T cells are of growing interest in the design of new strategies of immunotherapy. We show that the Butyrophilin3A (BTN3A, CD277) subfamily is a critical determinant of Vγ9Vδ2 TCR-mediated recognition of human primary AML blasts . Moreover, anti-BTN3A 20.1 agonist monoclonal antibodies (mAbs) can trigger BTN3A on AML blasts leading to further enhanced Vγ9Vδ2 T cell-mediated killing, but this mAb had no enhancing effect upon NK cell-mediated killing. We show that monocytic differentiation of primary AML blasts accounts for their AminoBisphosphonate (N-BP)-mediated sensitization to Vγ9Vδ2 T cells. In addition, anti-BTN3A 20.1 mAbs could specifically sensitize resistant blasts to Vγ9Vδ2 T cells lysis and overcome the poor effect of N-BP treatment on those blasts. We confirmed the enhancement of Vγ9Vδ2 T cells activity by anti-BTN3A 20.1 mAb using a human AML xenotransplantation mouse model. We showed that anti-BTN3A 20.1 mAb combined with Vγ9Vδ2 T cells immunotherapy could increase animal survival and decrease the leukemic burden in blood and bone marrow. These findings could be of great interest in the design of new immunotherapeutic strategies for treating AML.
鉴于Vγ9Vδ2 T细胞在体内外均具有公认的杀伤急性髓系白血病（AML）原始细胞的能力，其在新型免疫治疗策略设计中的应用正受到越来越多的关注。我们发现，嗜乳脂蛋白3A（BTN3A，CD277）亚家族是Vγ9Vδ2 TCR介导的对人原发性AML原始细胞识别的关键决定因素。此外，抗BTN3A 20.1激动剂单克隆抗体（mAb）可触发AML原始细胞上的BTN3A，导致Vγ9Vδ2 T细胞介导的杀伤作用进一步增强，但该mAb对NK细胞介导的杀伤没有增强作用。我们发现，原发性AML原始细胞的单核细胞分化是其氨基双膦酸盐（N-BP）介导的对Vγ9Vδ2 T细胞致敏的原因。此外，抗BTN3A 20.1 mAb可使耐药原始细胞对Vγ9Vδ2 T细胞裂解产生特异性致敏，并克服N-BP治疗对这些原始细胞的不良影响。我们使用人AML异种移植小鼠模型证实了抗BTN3A 20.1 mAb可增强Vγ9Vδ2 T细胞的活性。我们发现，抗BTN3A 20.1 mAb与Vγ9Vδ2 T细胞免疫疗法联合应用可提高动物存活率，并降低血液和骨髓中的白血病负担。这些发现可能对设计治疗AML的新型免疫治疗策略具有重要意义。
