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NOX2-dependent immunosuppression in chronic myelomonocytic leukemia

Aurelius, Johan ; Hallner, Alexander ; Werlenius, Olle ; Riise, Rebecca ; Möllgård, Lars ; Brune, Mats ; Hansson, Markus LU orcid ; Martner, Anna ; Thorén, Fredrik B and Hellstrand, Kristoffer (2017) In Journal of Leukocyte Biology 102(2). p.459-466
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... (More)

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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; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell Separation, Flow Cytometry, Humans, Immunophenotyping, Leukemia, Myelomonocytic, Chronic, Membrane Glycoproteins, Microscopy, Confocal, Myeloid Cells, NADPH Oxidase, Reactive Oxygen Species, Tumor Escape, Journal Article
in
Journal of Leukocyte Biology
volume
102
issue
2
pages
459 - 466
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85020479854
  • pmid:28292946
ISSN
1938-3673
DOI
10.1189/jlb.5VMA1116-454R
language
English
LU publication?
yes
id
5b32a18a-dda5-4c45-80d5-d14bb33047b1
date added to LUP
2017-10-03 08:56:09
date last changed
2025-01-20 22:59:50
@article{5b32a18a-dda5-4c45-80d5-d14bb33047b1,
  abstract     = {{<p>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.</p>}},
  author       = {{Aurelius, Johan and Hallner, Alexander and Werlenius, Olle and Riise, Rebecca and Möllgård, Lars and Brune, Mats and Hansson, Markus and Martner, Anna and Thorén, Fredrik B and Hellstrand, Kristoffer}},
  issn         = {{1938-3673}},
  keywords     = {{Cell Separation; Flow Cytometry; Humans; Immunophenotyping; Leukemia, Myelomonocytic, Chronic; Membrane Glycoproteins; Microscopy, Confocal; Myeloid Cells; NADPH Oxidase; Reactive Oxygen Species; Tumor Escape; Journal Article}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{459--466}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Leukocyte Biology}},
  title        = {{NOX2-dependent immunosuppression in chronic myelomonocytic leukemia}},
  url          = {{http://dx.doi.org/10.1189/jlb.5VMA1116-454R}},
  doi          = {{10.1189/jlb.5VMA1116-454R}},
  volume       = {{102}},
  year         = {{2017}},
}