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The Novel Toll-Like Receptor 2 Agonist SUP3 Enhances Antigen Presentation and T Cell Activation by Dendritic Cells.

ABSTRACT: Dendritic cells (DCs) are highly specialized antigen-presenting cells that play crucial roles in innate and adaptive immunity. Previous studies suggested that Toll-like receptor (TLR) agonists could be used as potential adjuvants, as activation of TLRs can boost DC-induced immune responses. TLR2 agonists have been shown to enhance DC-mediated immune responses. However, classical TLR2 agonists such as Pam3CSK4 are not stable enough in vivo, which limits their clinical applications. In this study, a novel structurally stable TLR2 agonist named SUP3 was designed. Functional analysis showed that SUP3 induced much stronger antitumor response than Pam3CSK4 by promoting cytotoxic T lymphocytes activation in vivo. This effect was achieved through the following mechanisms: SUP3 strongly enhanced the ability of antigen cross-presentation by DCs and subsequent T cell activation. SUP3 upregulated the expression of costimulatory molecules on DCs and increased antigen deposition in draining lymph nodes. More interestingly, SUP3 induced less amount of pro-inflammatory cytokine production in vivo compared to other TLR agonists such as lipopolysaccharide. Taken together, SUP3 could serve as a novel promising immune adjuvant in vaccine development and immune modulations.

SUBMITTER: Guo X

PROVIDER: S-EPMC5318439 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Novel Toll-Like Receptor 2 Agonist SUP3 Enhances Antigen Presentation and T Cell Activation by Dendritic Cells.

Guo Xueheng X Wu Ning N Shang Yingli Y Liu Xin X Wu Tao T Zhou Yifan Y Liu Xin X Huang Jiaoyan J Liao Xuebin X Wu Li L

Frontiers in immunology 20170221

Dendritic cells (DCs) are highly specialized antigen-presenting cells that play crucial roles in innate and adaptive immunity. Previous studies suggested that Toll-like receptor (TLR) agonists could be used as potential adjuvants, as activation of TLRs can boost DC-induced immune responses. TLR2 agonists have been shown to enhance DC-mediated immune responses. However, classical TLR2 agonists such as Pam3CSK4 are not stable enough <i>in vivo</i>, which limits their clinical applications. In this ...[more]

PMID: 28270814

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Project description:BackgroundDendritic cells (DCs) are professional antigen presenting cells that initiate immune defense to pathogens and tumor cells. Human tumors contain only few DCs that mostly display a non-activated phenotype. Hence, activation of tumor-associated DCs may improve efficacy of cancer immunotherapies. Toll-like receptor (TLR) agonists and interferons are known to promote DC maturation. However, it is unclear if DCs in human tumors respond to activation signals and which stimuli induce the optimal activation of human tumor DCs.MethodsWe first screened combinations of TLR agonists, a STING agonist and interferons (IFNs) for their ability to activate human conventional DCs (cDCs). Two combinations: TL8-506 (a TLR8 agonist)+IFN-γ and TL8-506+Poly(I:C) (a TLR3 agonist) were studied in more detail. cDC1s and cDC2s derived from cord blood stem cells, blood or patient tumor samples were stimulated with either TL8-506+IFN-γ or TL8-506+Poly(I:C). Different activation markers were analyzed by ELISA, flow cytometry, NanoString nCounter Technology or single-cell RNA-sequencing. T cell activation and migration assays were performed to assess functional consequences of cDC activation.ResultsWe show that TL8-506 synergized with IFN-γ or Poly(I:C) to induce high expression of different chemokines and cytokines including interleukin (IL)-12p70 in human cord blood and blood cDC subsets in a combination-specific manner. Importantly, both combinations induced the activation of cDC subsets in patient tumor samples ex vivo. The expression of immunostimulatory genes important for anticancer responses including CD40, IFNB1, IFNL1, IL12A and IL12B were upregulated on stimulation. Furthermore, chemokines associated with CD8+ T cell recruitment were induced in tumor-derived cDCs in response to TL8-506 combinations. In vitro activation and migration assays confirmed that stimulated cDCs induce T cell activation and migration.ConclusionsOur data suggest that cord blood-derived and blood-derived cDCs are a good surrogate to study treatment responses in human tumor cDCs. While most cDCs in human tumors display a non-activated phenotype, TL8-506 combinations drive human tumor cDCs towards an immunostimulatory phenotype associated with Th1 responses on stimulation. Hence, TL8-506-based combinations may be promising candidates to initiate or boost antitumor responses in patients with cancer.

Dataset Information

The Novel Toll-Like Receptor 2 Agonist SUP3 Enhances Antigen Presentation and T Cell Activation by Dendritic Cells.

Publications

The Novel Toll-Like Receptor 2 Agonist SUP3 Enhances Antigen Presentation and T Cell Activation by Dendritic Cells.

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