Werlenius Olle, Aurelius Johan, Hallner Alexander, Akhiani Ali A, Simpanen Maria, Martner Anna, Andersson Per-Ola, Hellstrand Kristoffer, Thorén Fredrik B
Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.
TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Oncotarget. 2016 May 31;7(22):32046-53. doi: 10.18632/oncotarget.8769.
The antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells is assumed to contribute to the clinical efficacy of monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL) and other hematopoietic malignancies of B cell origin. We sought to determine whether reactive oxygen species (ROS)-producing monocytes regulate the ADCC of NK cells against primary CLL cells using anti-CD20 as the linking antibody. The monoclonal CD20 antibodies rituximab and ofatumumab were found to trigger substantial release of ROS from monocytes. Antibody-exposed monocytes induced NK cell apoptosis and restricted NK cell-mediated ADCC against autologous CLL cells. The presence of inhibitors of ROS formation and scavengers of ROS preserved NK cell viability and restored NK cell-mediated ADCC against primary CLL cells. We propose that limiting the antibody-induced induction of immunosuppressive ROS may improve the anti-leukemic efficacy of anti-CD20 therapy in CLL.
自然杀伤（NK）细胞的抗体依赖性细胞毒性（ADCC）被认为有助于单克隆抗体（mAb）在慢性淋巴细胞白血病（CLL）及其他B细胞起源的血液系统恶性肿瘤中的临床疗效。我们试图确定产生活性氧（ROS）的单核细胞是否利用抗CD20作为连接抗体来调节NK细胞对原发性CLL细胞的ADCC。发现单克隆CD20抗体利妥昔单抗和奥法木单抗可触发单核细胞大量释放ROS。抗体处理过的单核细胞诱导NK细胞凋亡，并限制NK细胞介导的对自体CLL细胞的ADCC。ROS形成抑制剂和ROS清除剂的存在可维持NK细胞活力，并恢复NK细胞介导的对原发性CLL细胞的ADCC。我们提出，限制抗体诱导的免疫抑制性ROS的产生可能会提高抗CD20疗法在CLL中的抗白血病疗效。
