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NOX2-dependent immunosuppression in chronic myelomonocytic leukemia

Journal article
Authors Johan Aurelius
Alexander Hallner
Olle Werlenius
Rebecca E Riise
L. Mollgard
M. Brune
M. Hansson
Anna Martner
Fredrik Bergh Thorén
Kristoffer Hellstrand
Published in Journal of Leukocyte Biology
Volume 102
Issue 2
Pages 459-466
ISSN 0741-5400
Publication year 2017
Published at Sahlgrenska Cancer Center
Pages 459-466
Language en
Links doi.org/10.1189/jlb.5VMA1116-454R
Keywords CMML, reactive oxygen species, NK cells, ROS, T cells, MDS/MPN, acute myeloid-leukemia, natural-killer-cells, reactive oxygen, metabolites, nk cells, histaminergic regulation, cytotoxic lymphocytes, oxidative stress, free survival, expression, apoptosis, Cell Biology, Hematology, Immunology, llin p, 1991, cell biochemistry and function, v9, p29
Subject categories Cancer and Oncology

Abstract

Chronic myelomonocytic leukemia (CMML) is a myeloproliferative and myelodysplastic neoplasm with few treatment options and dismal prognosis. The role of natural killer (NK) cells and other antileukemic lymphocytes in CMML is largely unknown. We aimed to provide insight into the mechanisms of immune evasion in CMML with a focus on immunosuppressive reactive oxygen species (ROS) formed by the myeloid cell NADPH oxidase-2 (NOX2). The dominant population of primary human CMML cells was found to express membrane-bound NOX2 and to release ROS, which, in turn, triggered extensive PARP-1-dependent cell death in cocultured NK cells, CD8(+) T effector memory cells, and CD8(+) T effector cells. Inhibitors of ROS formation and scavengers of extracellular ROS prevented CMML cell-induced lymphocyte death and facilitated NK cell degranulation toward Ab-coated, primary CMML cells. In patients with CMML, elevation of immature cell counts (CD34(+)) in blood was associated with reduced expression of several NK cell-activating receptors. We propose that CMML cells may use extracellular ROS as a targetable mechanism of immune escape.

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