title: ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment.
abstract: Tumor microenvironment of solid tumors is characterized by a strikingly high concentration of adenosine and ATP. Physiological significance of this biochemical feature is unknown, but it has been suggested that it may affect infiltrating immune cell responses and tumor progression. There is increasing awareness that many of the effects of extracellular ATP on tumor and inflammatory cells are mediated by the P2X7 receptor (P2X7R). Aim of this study was to investigate whether: (i) extracellular ATP is a component of neuroblastoma (NB) microenvironment, (ii) myeloid-derived suppressor cells (MDSCs) express functional P2X7R and (iii) the ATP/P2X7R axis modulates MDSC functions. Our results show that extracellular ATP was detected in NB microenvironment in amounts that increased in parallel with tumor progression. The percentage of CD11b(+)/Gr-1(+) cells was higher in NB-bearing mice compared with healthy animals. Within the CD11b/Gr-1(+) population, monocytic MDSCs (M-MDSCs) produced higher levels of reactive oxygen species (ROS), arginase-1 (ARG-1), transforming growth factor-β1 (TGF-β1) and stimulated more potently in vivo tumor growth, as compared with granulocytic MDSCs (G-MDSCs). P2X7R of M-MDSCs was localized at the plasma membrane, coupled to increased functionality, upregulation of ARG-1, TGF-β1 and ROS. Quite surprisingly, the P2X7R in primary MDSCs as well as in the MSC-1 and MSC-2 lines was uncoupled from cytotoxicity. This study describes a novel scenario in which MDSC immunosuppressive functions are modulated by the ATP-enriched tumor microenvironment.
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bianchi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Vuerich
authors.affiliation: 1] Department of Life Sciences and Biotechnology, Biochemistry and Molecular Biology Section, University of Ferrara, Ferrara, Italy [2] Laboratory of Clinical Chemistry and Microbiology, Azienda Ospedaliero-Universitaria, Sant'Anna Hospital, Ferrara, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Pellegatti
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Marimpietri
authors.affiliation: Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Emionite
authors.affiliation: Istituto Oncologico Veneto, IRCCS, Padova, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Marigo
authors.affiliation: Department of Pathology and Diagnostic, Immunology Section, Verona University Hospital, Verona, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Di Virgilio
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Pistoia
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Raffaghello
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001119:Arginase / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D039481:CD11b Antigen; D016207:Cytokines; C503133:Gr-1 protein, mouse; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D017382:Reactive Oxygen Species; D019707:Receptors, Chemokine; D058486:Receptors, Purinergic P2X7; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D000255:Adenosine Triphosphate; C544448:Arg1 protein, mouse; D001119:Arginase