title: NOX2-dependent immunosuppression in chronic myelomonocytic leukemia.
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.
authors.affiliation: Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.|TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Johan
authors.initials: J
authors.lastname: Aurelius
authors.affiliation: TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hallner
authors.affiliation: Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.|TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Olle
authors.initials: O
authors.lastname: Werlenius
authors.affiliation: TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Riise
authors.affiliation: Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Möllgård
authors.affiliation: Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Brune
authors.affiliation: Department of Hematology, Skåne University Hospital, Scania, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Hansson
authors.affiliation: TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Martner
authors.affiliation: TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Fredrik B
authors.initials: FB
authors.lastname: Thorén
authors.affiliation: TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; and kristoffer.hellstrand@gu.se.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Hellstrand
mesh_terms: D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D015477:Leukemia, Myelomonocytic, Chronic / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000276:immunology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: CMML; MDS/MPN; NK cells; ROS; T cells; reactive oxygen species