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

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

Enhancement of antitumor vaccination by targeting dendritic cell-related IL-10

Understanding mechanisms associated to dendritic cell (DC) functions has allowed developing new antitumor therapeutic vaccination strategies. However, these vaccines have demonstrated limited clinical results. Although the low immunogenicity of tumor antigens used and the presence of tumor-associated suppressive factors may in part account for these results, intrinsic vaccine-related factors may also be involved. Vaccines modulate DC functions by inducing activating and inhibitory signals that determine ensuing T cell responses. In this mini review, we focus on IL-10, inhibitory cytokine induced in DC upon vaccination, which defines a suppressive cell subset, discussing its implications as a potential target in combined vaccination immunotherapies

Enhancement of antitumor vaccination by targeting dendritic cell-related IL-10

Understanding mechanisms associated to dendritic cell (DC) functions has allowed developing new antitumor therapeutic vaccination strategies. However, these vaccines have demonstrated limited clinical results. Although the low immunogenicity of tumor antigens used and the presence of tumor-associated suppressive factors may in part account for these results, intrinsic vaccine-related factors may also be involved. Vaccines modulate DC functions by inducing activating and inhibitory signals that determine ensuing T cell responses. In this mini review, we focus on IL-10, inhibitory cytokine induced in DC upon vaccination, which defines a suppressive cell subset, discussing its implications as a potential target in combined vaccination immunotherapies

Silk fibroin as sustainable advanced material: material properties and characteristics, processing, and applications

Bio-based resources are proposed as next-generation materials for advanced application. Among them, silk fibroin, a protein-based material generally obtained from Bombyx mori cocoons, is considered to play an increasing role in the development of a more sustainable generation of devices. In this review, the silk fibroin molecular structure and its original properties are presented, together with a wide overview of the available modifications and processing methods to reach custom structural and functional variations.The authors thank the FCT (Fundação para a Ciência e Tecnologia) for financial support under the framework of Strategic Funding grants UID/FIS/04650/2019, and UID/EEA/04436/2019; and project PTDC/FIS-MAC/28157/2017. The author also thanks the FCT for investigator FCT contract 2020.04028.CEECIND (C.M.C.) as well as by the POCH and European Union. The authors thank funding by the Spanish State Research Agency (AEI) and the European Regional Development Fund (ERFD) through the project PID2019-106099RB-C43 / AEI / 10.13039/501100011033 and from the Basque Government Industry and Education Departments under the ELKARTEK program, respectivel

The Toll like receptor 4 ligand cold-inducible RNA-binding protein as vaccination platform against cancer

Tumor infiltrating lymphocytes have been associated with a better prognostic and with higher response rates in patients treated with checkpoint inhibiting antibodies, suggesting that strategies promoting tumor inflammation may enhance the efficacy of these currently available therapies. Our aim was thus to develop a new vaccination platform based on cold-inducible RNA binding protein (CIRP), an endogenous TLR4 ligand generated during inflammatory processes, and characterize whether it was amenable to combination with checkpoint inhibitors. In vitro, CIRP induced dendritic cell activation, migration and enhanced presentation of CIRP-bound antigens to T-cells. Accordingly, antigen conjugation to CIRP conferred immunogenicity, dependent on immunostimulatory and antigen-targeting capacities of CIRP. When applied in a therapeutic setting, vaccination led to CD8-dependent tumor rejection in several tumor models. Moreover, immunogenicity of this vaccination platform was enhanced not only by combination with additional adjuvants, but also with antibodies blocking PD-1/PD-L1, CTLA-4 and IL-10, immunosuppressive molecules usually present in the tumor environment and also induced by the vaccine. Therefore, priming with a CIRP-based vaccine combined with immune checkpoint-inhibiting antibodies rejected established B16-OVA tumors. Finally, equivalent activation and T-cell stimulatory effects were observed when using CIRP in vitro with human cells, suggesting that CIRP-based vaccination strategies could be a valuable clinical tool to include in combinatorial immunotherapeutic strategies in cancer patients

Monocyte-derived dendritic cells from HCV-infected patients transduced with an adenovirus expressing NS3 are functional when stimulated with the TLR3 ligand poly(I:C)

Dendritic cells (DC) transfected with an adenovirus encoding hepatitis C virus (HCV) NS3 protein (AdNS3) induce potent antiviral immune responses when used to immunize mice. However, in HCV infected patients, controversial results have been reported regarding the functional properties of monocyte-derived DC (MoDC), a cell population commonly used in DC vaccination protocols. Thus, with the aim of future vaccination studies we decided to characterize MoDC from HCV patients transfected with AdNS3 and stimulated with the TLR3 ligand poly(I:C). Phenotypic and functional properties of these cells were compared with those from MoDC obtained from uninfected individuals. PCR analysis showed that HCV RNA was negative in MoDC from patients after the culture period. Also, phenotypic analysis of these cells showed lower expression of CD80, CD86, and CD40, but similar expression of HLA-DR molecules as compared to MoDC from uninfected individuals. Functional assays of MoDC obtained from patients and controls showed a similar ability to activate allogeneic lymphocytes or to produce IL-12 and IL-10, although lower IFN-alpha levels were produced by cells from HCV patients after poly(I:C) stimulation. Moreover, both groups of MoDC induced similar profiles of IFN-gamma and IL-5 after stimulation of allogeneic T-cells. Finally, migration assays did not reveal any difference in their ability to respond to CCL21 chemokine. In conclusion, MoDC from HCV patients are functional after transduction with AdNS3 and stimulation with poly(I:C). These findings suggest that these cells may be useful for therapeutic vaccination in chronic HCV infection

Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model

Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFN-γ production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection. These results provide a rationale for testing Belinostat in combination with checkpoint inhibitors to enhance their therapeutic activity in patients with HCC