Oncotarget

Research Papers:

IL-10 expression defines an immunosuppressive dendritic cell population induced by antitumor therapeutic vaccination

Diana Llopiz, Marta Ruiz, Stefany Infante, Lorea Villanueva, Leyre Silva, Sandra Hervas-Stubbs, Diego Alignani, Elizabeth Guruceaga, Juan J. Lasarte and Pablo Sarobe _

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Oncotarget. 2017; 8:2659-2671. https://doi.org/10.18632/oncotarget.13736

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Abstract

Diana Llopiz1,2, Marta Ruiz1,2, Stefany Infante1, Lorea Villanueva1, Leyre Silva1,2, Sandra Hervas-Stubbs1,2, Diego Alignani2,3, Elizabeth Guruceaga2,4, Juan J. Lasarte1,2, Pablo Sarobe1,2

1Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

2IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

3Cytometry Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

4Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

Correspondence to:

Pablo Sarobe, email: [email protected]

Keywords: dendritic cells, therapeutic vaccination, IL-10, PD-L1, immunoregulation

Received: September 14, 2016     Accepted: November 22, 2016     Published: December 01, 2016

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.


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