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.
Highlights
The tumor microenvironment is characterized by the presence of immunosuppressive molecules which induce inhibitory effects on antitumor immunity [1]
Mice were vaccinated with OVA+Imiquimod and compared to controls groups of untreated mice (UT) or mice vaccinated with OVA+poly(I:C), a vaccine in which IL-10 blockade did not provide any antitumor benefit [23]
We have analyzed the role of IL-10, a cytokine with controversial effects on tumor immunity [16], reported as detrimental for T-cell priming during therapeutic vaccination [23, 25]
Summary
The tumor microenvironment is characterized by the presence of immunosuppressive molecules which induce inhibitory effects on antitumor immunity [1] This microenvironment precludes correct activation of antigen-presenting cells (APC) responsible for priming T-cell responses [2] and the effector phase of tumorspecific lymphocytes [3, 4]. Characterization of these immunosuppressive molecules has allowed the design of new therapies aimed at blocking their inhibitory functions, leading to activation of antitumor immunity and efficient clinical effects [5, 6]. Besides inhibitory effects on APC with the concomitant down-regulation of T-cell activation, www.impactjournals.com/oncotarget
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