title: Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer.
abstract: Tumor-derived microvesicles (TD-MVs) are key mediators which are shed by cancer cells and can sensitize neighboring cells in the tumor microenvironment. TD-MVs are extracellular vesicles composed of exosomes and MVs and promote cancer invasion and metastasis. Intratumoral hypoxia is an integral component of all solid tumors. The relationship between hypoxic tumor-shed MVs and NK-mediated cytotoxicity remains unknown. In this paper, we reported that MVs derived from hypoxic tumor cells qualitatively differ from those derived from normoxic tumor cells. Using multiple tumor models, we showed that hypoxic MVs inhibit more NK cell function as compared to normoxic MVs. Hypoxic TD-MVs package two immunosuppressive factors involved in the impairment of natural killer (NK) cell cytotoxicity against different tumor cellsin vitroandin vivo. We showed that following their uptake by NK cells, hypoxic TD-MVs transfer TGF-β1 to NK cells, decreasing the cell surface expression of the activating receptor NKG2D, thereby inhibiting NK cell function. MicroRNA profiling revealed the presence of high levels of miR-210 and miR-23a in hypoxic TD-MVs. We demonstrated that miR-23a in hypoxic TD-MVs operates as an additional immunomosuppressive factor, since it directly targets the expression of CD107a in NK cells. To our knowledge, this is the first study to show that hypoxic tumor cells by secreting MVs can educate NK cells and decrease their antitumor immune response. This study highlights the existence of a novel mechanism of immune suppression mediated by hypoxic TD-MVs and further improves our understanding of the immunosuppressive mechanisms prevailing in the hypoxic tumor microenvironment.
authors.affiliation: INSERM U1186, Gustave Roussy Cancer Campus, Villejuif, France; Laboratory of Experimental Cancer Research, Hemato-Oncology, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg.
authors.forename: Guy
authors.initials: G
authors.lastname: Berchem
authors.affiliation: INSERM U1186, Gustave Roussy Cancer Campus , Villejuif, France.
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.affiliation: Laboratory of Experimental Cancer Research, Hemato-Oncology, Department of Oncology, Luxembourg Institute of Health , Luxembourg City, Luxembourg.
authors.forename: Manon
authors.initials: M
authors.lastname: Bosseler
authors.affiliation: Laboratory of Experimental Cancer Research, Hemato-Oncology, Department of Oncology, Luxembourg Institute of Health , Luxembourg City, Luxembourg.
authors.forename: Jerome
authors.initials: J
authors.lastname: Paggetti
authors.affiliation: Maintenance des génomes et microscopies moléculaires UMR 8126, Signalisation, noyaux et innovations en cancérologie, CNRS-Université Paris Sud, Gustave Roussy Cancer Campus , Villejuif, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Baconnais
authors.affiliation: Maintenance des génomes et microscopies moléculaires UMR 8126, Signalisation, noyaux et innovations en cancérologie, CNRS-Université Paris Sud, Gustave Roussy Cancer Campus , Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Le Cam
authors.affiliation: INSERM U1186, Gustave Roussy Cancer Campus , Villejuif, France.
authors.forename: Arash
authors.initials: A
authors.lastname: Nanbakhsh
authors.affiliation: Laboratory of Experimental Cancer Research, Hemato-Oncology, Department of Oncology, Luxembourg Institute of Health , Luxembourg City, Luxembourg.
authors.forename: Etienne
authors.initials: E
authors.lastname: Moussay
authors.affiliation: INSERM U1186, Gustave Roussy Cancer Campus , Villejuif, France.
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.affiliation: Laboratory of Experimental Cancer Research, Hemato-Oncology, Department of Oncology, Luxembourg Institute of Health , Luxembourg City, Luxembourg.
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.affiliation: INSERM U1186, Gustave Roussy Cancer Campus , Villejuif, France.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
keywords: Hypoxia; LAMP-1; NKG2D; TGF-β; miR-23a; microvesicles; natural killer cells