title: Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC.
abstract: In certain infection sites or tumor tissues, the disruption of homeostasis can give rise to a hypoxic microenvironment, which, in turn, can alter the function of different immune cell types and favor the progression of the disease. Natural killer (NK) cells are directly involved in the elimination of virus-infected or transformed cells, however it is unknown whether their function is affected by hypoxia or not. In this study, we show that NK cells adapt to a hypoxic environment by upregulating the hypoxia-inducible factor 1α. However, NK cells lose their ability to upregulate the surface expression of the major activating NK-cell receptors (NKp46, NKp30, NKp44, and NKG2D) in response to IL-2 (or other activating cytokines, including IL-15, IL-12, and IL-21). These altered phenotypic features correlate with reduced responses to triggering signals resulting in impaired capability of killing infected or tumor target cells. Remarkably, hypoxia does not significantly alter the surface density and the triggering function of the Fc-γ receptor CD16, thus allowing NK cells to maintain their capability of killing target cells via antibody-dependent cellular cytotoxicity. This finding offers an important clue for exploitation of NK cell in antibody-based immunotherapy of cancer.
authors.affiliation: Dipartimento di Medicina Sperimentale, Università di Genova, Genova, Italy.
authors.forename: Mirna
authors.initials: M
authors.lastname: Balsamo
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pietra
authors.forename: Federica
authors.initials: F
authors.lastname: Raggi
authors.forename: Fabiola
authors.initials: F
authors.lastname: Blengio
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Bosco
authors.forename: Massimo
authors.initials: M
authors.lastname: Vitale
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000276:immunology; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D016207:Cytokines / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D000860:Hypoxia / Q000276:immunology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D055636:Receptors, Natural Cytotoxicity Triggering / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D055636:Receptors, Natural Cytotoxicity Triggering
keywords: ADCC; Hypoxia; NK cells; Tumor Escape; Tumor Microenvironment