title: IL-10 expression defines an immunosuppressive dendritic cell population induced by antitumor therapeutic vaccination.
abstract: Vaccination induces immunostimulatory signals that are often accompanied by regulatory mechanisms such as IL-10, which control T-cell activation and inhibit vaccine-dependent antitumor therapeutic effect. Here we characterized IL-10-producing cells in different tumor models treated with therapeutic vaccines. Although several cell subsets produced IL-10 irrespective of treatment, an early vaccine-dependent induction of IL-10 was detected in dendritic cells (DC). IL-10 production defined a DC population characterized by a poorly mature phenotype, lower expression of T-cell stimulating molecules and upregulation of PD-L1. These IL-10+ DC showed impaired in vitro T-cell stimulatory capacity, which was rescued by incubation with IL-10R and PD-L1-inhibiting antibodies. In vivo IL-10 blockade during vaccination decreased the proportion of IL-10+ DC and improved their maturation, without modifying PD-L1 expression. Similarly, PD-L1 blockade did not affect IL- 10 expression. Interestingly, vaccination combined with simultaneous blockade of IL-10 and PD-L1 induced stronger immune responses, resulting in a higher therapeutic efficacy in tumor-bearing mice. These results show that vaccine-induced immunoregulatory IL- 10+ DC impair priming of antitumor immunity, suggesting that therapeutic vaccination protocols may benefit from combined targeting of inhibitory molecules expressed by this DC subset.
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Llopiz
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Stefany
authors.initials: S
authors.lastname: Infante
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Lorea
authors.initials: L
authors.lastname: Villanueva
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Leyre
authors.initials: L
authors.lastname: Silva
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.affiliation: IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.|Cytometry Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Alignani
authors.affiliation: IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.|Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Guruceaga
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lasarte
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Sarobe
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D060890:B7-H1 Antigen; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000077271:Imiquimod; D056747:Immunomodulation; D016130:Immunophenotyping; D007167:Immunotherapy; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014611:Vaccination; D023041:Xenograft Model Antitumor Assays
chemical_list: D000634:Aminoquinolines; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019496:Cancer Vaccines; D016753:Interleukin-10; D000077271:Imiquimod
keywords: IL-10; PD-L1; dendritic cells; immunoregulation; therapeutic vaccination