Reactive oxygen species induced by therapeutic CD20 antibodies inhibit natural killer cell-mediated antibody-dependent cellular cytotoxicity against primary CLL cells
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Olle Werlenius1,2, Johan Aurelius1,2, Alexander Hallner2, Ali A. Akhiani2, Maria Simpanen2, Anna Martner2, Per-Ola Andersson3, Kristoffer Hellstrand2 and Fredrik B. Thorén2
1 Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden
2 TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
3 Department of Medicine, Södra Älvsborgs Hospital, Borås, Sweden
Fredrik B. Thorén, email:
Keywords: monoclonal antibodies, reactive oxygen species, immunotherapy, NK cells, NOX2
Received: March 31, 2016 Accepted: April 03, 2016 Published: April 16, 2016
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.
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