NOX2-dependent immunosuppression in chronic myelomonocytic leukemia

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

Nyckelord

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

Cell Separation

Flow Cytometry

Humans

Immunophenotyping

Leukemia, Myelomonocytic, Chronic

Membrane Glycoproteins

Microscopy, Confocal

Myeloid Cells

NADPH Oxidase

Reactive Oxygen Species

Tumor Escape

Journal Article

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)