title: Intravenous immunoglobulin promotes antitumor responses by modulating macrophage polarization.
abstract: Intravenous Igs (IVIg) therapy is widely used as an immunomodulatory strategy in inflammatory pathologies and is suggested to promote cancer regression. Because progression of tumors depends on their ability to redirect the polarization state of tumor-associated macrophages (from M1/immunogenic/proinflammatory to M2/anti-inflammatory), we have evaluated whether IVIg limits tumor progression and dissemination through modulation of macrophage polarization. In vitro, IVIg inhibited proinflammatory cytokine production from M1 macrophages and induced a M2-to-M1 polarization switch on human and murine M2 macrophages. In vivo, IVIg modified the polarization of tumor-associated myeloid cells in a Fcεr1γ chain-dependent manner, modulated cytokine blood levels in tumor-bearing animals, and impaired tumor progression via FcγRIII (CD16), FcγRIV, and FcRγ engagement, the latter two effects being macrophage mediated. Therefore, IVIg immunomodulatory activity is dependent on the polarization state of the responding macrophages, and its ability to trigger a M2-to-M1 macrophage polarization switch might be therapeutically useful in cancer, in which proinflammatory or immunogenic functions should be promoted.
authors.affiliation: Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Cientificas, Madrid 28040, Spain; ads@cib.csic.es acorbi@cib.csic.es.
authors.forename: Angeles
authors.initials: A
authors.lastname: Domínguez-Soto
authors.affiliation: Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Cientificas, Madrid 28040, Spain;
authors.forename: Mateo
authors.initials: M
authors.lastname: de las Casas-Engel
authors.affiliation: Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid 28040, Spain;
authors.forename: Rafael
authors.initials: R
authors.lastname: Bragado
authors.affiliation: Center for Applied Medical Research, Pamplona 31009, Spain;
authors.forename: José
authors.initials: J
authors.lastname: Medina-Echeverz
authors.affiliation: Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Cientificas, Madrid 28040, Spain;
authors.forename: Laura
authors.initials: L
authors.lastname: Aragoneses-Fenoll
authors.affiliation: Centro de Biología Molecular, Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Madrid 28049, Spain;
authors.forename: Enrique
authors.initials: E
authors.lastname: Martín-Gayo
authors.affiliation: Department of Molecular Cell Biology, Free University Medical Center, Amsterdam 1081, the Netherlands;
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: Center for Applied Medical Research, Pamplona 31009, Spain;
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.affiliation: Centro de Biología Molecular, Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Madrid 28049, Spain;
authors.forename: María L
authors.initials: ML
authors.lastname: Toribio
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid 28040, Spain;
authors.forename: María A
authors.initials: MA
authors.lastname: Moro
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid 28040, Spain;
authors.forename: Isabel
authors.initials: I
authors.lastname: Cuartero
authors.affiliation: Instituto de Investigaciones Biomédicas Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Madrid 28029, Spain; Unidad Asociada de Biomedicina, Consejo Superior de Investigaciones Cientificas-Universidad de Las Palmas de Gran Canarias 35001, Spain;
authors.forename: Antonio
authors.initials: A
authors.lastname: Castrillo
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain;
authors.forename: David
authors.initials: D
authors.lastname: Sancho
authors.affiliation: Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico;
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Torres
authors.affiliation: Institut Pasteur, Département d'Immunologie, Unité des Anticorps en Thérapie et Pathologie, Paris 75015, France; INSERM U760, Paris 75015, France; and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bruhns
authors.affiliation: Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sánchez-Ramón
authors.affiliation: Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Cientificas, Madrid 28040, Spain; ads@cib.csic.es acorbi@cib.csic.es.
authors.forename: Angel L
authors.initials: AL
authors.lastname: Corbí
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000145:classification / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C485700:Fcgr3 protein, mouse; C522404:Fcgr4 protein, mouse; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D017455:Receptors, IgE; D017452:Receptors, IgG