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Reactive oxygen species induced by therapeutic CD20 antibodies inhibit natural killer cell-mediated antibody-dependent cellular cytotoxicity against primary CLL cells

Journal article
Authors Olle Werlenius
Johan Aurelius
Alexander Hallner
Aliasghar Akhiani
Maria Simpanen
Anna Martner
Per-Ola Andersson
Kristoffer Hellstrand
Fredrik Bergh Thorén
Published in Oncotarget
Volume 7
Issue 22
Pages 32046-32053
ISSN 1949-2553
Publication year 2016
Published at Sahlgrenska Cancer Center
Pages 32046-32053
Language en
Links dx.doi.org/10.18632/oncotarget.8769
Keywords monoclonal antibodies, reactive oxygen species, immunotherapy, NK cells, NOX2, chronic lymphocytic-leukemia, nk cells, hydrogen-peroxide, suppressor-cells, b-cells, t-cell, apoptosis, monocytes, death, polymorphism
Subject categories Cancer and Oncology

Abstract

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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