Reactive oxygen species induced by therapeutic CD20 antibodies inhibit natural killer cell-mediated antibody-dependent cellular cytotoxicity against primary CLL cells.
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.
Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.|TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Olle
O
Werlenius
Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.|TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Johan
J
Aurelius
TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Alexander
A
Hallner
TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Ali A
AA
Akhiani
TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Maria
M
Simpanen
TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Anna
A
Martner
Department of Medicine, Södra Älvsborgs Hospital, Borås, Sweden.
Per-Ola
PO
Andersson
TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Kristoffer
K
Hellstrand
TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Fredrik B
FB
Thorén
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism*; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018920:Coculture Techniques; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000069283:Rituximab / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D000074322:Antineoplastic Agents, Immunological; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D000069283:Rituximab; C527517:ofatumumab
NK cells; NOX2; immunotherapy; monoclonal antibodies; reactive oxygen species