title: Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination.
abstract: Blocking antibodies against immunosuppressive molecules have shown promising results in cancer patients. However, there are not enough data to define those conditions dictating treatment efficacy. In this scenario, IL-10 is a cytokine with controversial effects on tumor growth. Thus, our aim was to characterize in which setting IL-10 blockade may potentiate the beneficial effects of a therapeutic vaccine In the IL-10-expressing B16-OVA and TC-1 P3 (A15) tumor models, therapeutic vaccination with tumor antigens plus the TLR7 ligand Imiquimod increased IL-10 production. Although blockade of IL-10 signal with anti-IL-10R antibodies did not inhibit tumor growth, when combined with vaccination it enhanced tumor rejection, associated with stronger innate and adaptive immune responses. Interestingly, a similar enhancement on immune responses was observed after simultaneous vaccination and IL-10 blockade in naive mice. However, when using vaccines containing as adjuvants the TLR3 ligand poly(I:C) or anti-CD40 agonistic antibodies, despite tumor IL-10 expression, anti-IL-10R antibodies did not provide any beneficial effect on tumor growth and antitumor immune responses. Of note, as opposed to Imiquimod, vaccination with this type of adjuvants did not induce IL-10 and correlated with a lack ofin vitroIL-10 production by dendritic cells (DC). Finally, in B16-OVA-bearing mice, blockade of IL-10 during therapeutic vaccination with a multiple adjuvant combination (MAC) with potent immunostimulatory properties but still inducing IL-10 led to superior antitumor immunity and complete tumor rejection. These results suggest that for therapeutic antitumor vaccination, blockade of vaccine-induced IL-10 is more relevant than tumor-associated IL-10.
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.
authors.forename: Fernando
authors.initials: F
authors.lastname: Aranda
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra , Pamplona, Spain.
authors.forename: Nancy
authors.initials: N
authors.lastname: Díaz-Valdés
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: Virginia
authors.initials: V
authors.lastname: Belsúe
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 José
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
keywords: Adjuvant; Interleukin-10; antitumor immunity; blockade; dendritic cells; therapeutic vaccination