title: Neuroblastoma-derived TGF-β1 modulates the chemokine receptor repertoire of human resting NK cells.
abstract: In this study, we show that neuroblastoma (NB) cell conditioning affects the chemokine receptor repertoire of human resting NK cells. In particular, NB cells upregulated the expression of CXCR4 and CXCR3 in all NK cells and downregulated CX3CR1 in the CD56(dim) subset. On the contrary, the expression of CXCR1 and CCR7 remained unaltered. The phenomenon was dependent on the release by NB cells of TGF-β1, and rTGF-β1 induced a chemokine receptor repertoire identical to that of NB-conditioned NK cells. The immune modulatory role of TGF-β1 appears to be dose dependent because low amounts of the cytokine were sufficient to modulate CXCR4 and CX3CR1 expression, intermediate amounts modified that of CXCR3, and high amounts were necessary to downregulate the expression of the NKp30 activating receptor. Notably, a similar receptor modulation was observed in rTGF-β2-conditioned NK cells. Finally, the analysis of NK cells from patients with stage 4 NB suggests that NB conditioning could exert in vivo an immune modulatory effect resembling that emerged from in vitro experiments. Altogether our data propose a novel tumor escape-mechanism based on the modulation of chemokine receptors that play pivotal roles in NK cells bone marrow homing, egress, or recruitment into peripheral tissues.
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, 16132 Genoa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Castriconi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dondero
authors.forename: Francesca
authors.initials: F
authors.lastname: Bellora
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Aurora
authors.initials: A
authors.lastname: Castellano
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: Corrias
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.forename: Cristina
authors.initials: C
authors.lastname: Bottino
mesh_terms: D019002:CD56 Antigen; D000073883:CX3C Chemokine Receptor 1; D045744:Cell Line, Tumor; D002648:Child; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000096:biosynthesis; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000096:biosynthesis; D054367:Receptors, CXCR3 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis; D023062:Receptors, Interleukin-8A / Q000096:biosynthesis; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D019139:Tumor Escape; D015854:Up-Regulation
chemical_list: C515370:CCR7 protein, human; D019002:CD56 Antigen; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; C515187:CXCR3 protein, human; C527276:CXCR4 protein, human; C431710:NCR3 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1