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

Olle Werlenius,Fredrik B Thorén,Anna Martner,Alexander Hallner,Ali A Akhiani,Per-Ola Andersson,Johan Aurelius,Maria Simpanen,Kristoffer Hellstrand

doi:10.18632/oncotarget.8769

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.

Highlights

Subsets of cytotoxic leukocytes, including myeloid cells and natural killer (NK) cells, carry different Fcγ-receptors (FcγR) and may attach the Fc portion of IgG antibodies to exert cytotoxicity against cells expressing a specific antigen [1]
antibody-dependent cellular cytotoxicity (ADCC) is assumed to contribute to the clinical benefit of antibodies against CD20, such as rituximab (RTX) and ofatumumab (OFA), in B cell malignancies, and recent studies support that FcγR+ NK cells are pivotal for the anti-leukemic efficacy [2,3,4]
In a first series of experiments we investigated whether CD20 monoclonal antibodies (mAbs) mount an oxidative response from monocytes

Summary

Introduction

Subsets of cytotoxic leukocytes, including myeloid cells and NK cells, carry different Fcγ-receptors (FcγR) and may attach the Fc portion of IgG antibodies to exert cytotoxicity against cells expressing a specific antigen [1]. ADCC is assumed to contribute to the clinical benefit of antibodies against CD20, such as rituximab (RTX) and ofatumumab (OFA), in B cell malignancies, and recent studies support that FcγR+ NK cells are pivotal for the anti-leukemic efficacy [2,3,4]. We hypothesized that reducing myeloid cell-derived ROS may improve the anti-leukemic efficacy of CD20 antibodies and investigated the impact of human NOX2+ monocytes on ADCC against human primary CLL cells in the presence or absence of anti-CD20 and anti-oxidative compounds.

Results

Conclusion