Synergy of TLR3 and 7 ligands significantly enhances function of DCs to present inactivated PRRSV antigen through TRIF/MyD88-NF-κB signaling pathway

Hu, Yue; Xu, Cong; Chen, Lei; Qi, Jing; Wu, Xiangju; Zhou, Ming‐Ming; Yoo, Dongwan; Feng, Liang; Sun, Wenbo; Wu, Jiaqiang; Zhao, Xiaomin; Chen, Zhi; Yu, Jiang; Du, Yijun; Wang, Jinbao

doi:10.1038/srep23977

Cited by 29 publications

(29 citation statements)

References 55 publications

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“…A TLR3 ligand, poly I:C, among immunological adjuvants is a powerful agent to induce antitumor immunity by increasing IL‐12 production from dendritic cells in tumor‐bearing hosts . However, the TLR3/TRIF/MyD88‐NF‐kb signaling pathway in dendritic cells induces both IL‐6 and IL‐12 production . We confirmed that the IL‐6‐deficient condition promoted IL‐12 induction and the antitumor effect of immunoadjuvant therapy using poly I:C.…”

Section: Discussionsupporting

confidence: 69%

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Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

et al. 2017

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Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)‐6, a pleiotropic cytokine, is produced in the tumor‐bearing state. In the present study, we investigated the precise effects of IL‐6 on antitumor immunity and the subsequent tumorigenesis in tumor‐bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild‐type and IL‐6‐deficient mice. As a result, we found that tumor growth was decreased significantly in IL‐6‐deficient mice compared with wild‐type mice and the reduction was abrogated by depletion of CD8+ T cells. We further evaluated the immune status of tumor microenvironments and confirmed that mature dendritic cells, helper T cells and cytotoxic T cells were highly accumulated in tumor sites under the IL‐6‐deficient condition. In addition, higher numbers of interferon (IFN)‐γ‐producing T cells were present in the tumor tissues of IL‐6‐deficient mice compared with wild‐type mice. Surface expression levels of programmed death‐ligand 1 (PD‐L1) and MHC class I on CT26 cells were enhanced under the IL‐6‐deficient condition in vivo and by IFN‐γ stimulation in vitro. Finally, we confirmed that in vivo injection of an anti‐PD‐L1 antibody or a Toll‐like receptor 3 ligand, polyinosinic‐polycytidylic acid, effectively inhibited tumorigenesis under the IL‐6‐deficient condition. Based on these findings, we speculate that a lack of IL‐6 produced in tumor‐bearing host augments induction of antitumor effector T cells and inhibits tumorigenesis in vivo, suggesting that IL‐6 signaling may be a promising target for the development of effective cancer immunotherapies.

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Section: Discussionsupporting

confidence: 69%

“…Administration of immunological adjuvants occasionally induces IL‐6 production in vivo . As a therapeutic experiment, we injected poly I:C, a TLR3 ligand, into tumor‐bearing wild‐type and IL‐6 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

et al. 2017

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“…In contrast to swine immunization models, either a type 1 or a mixed type1/type 2 response is generally reported in mouse models when immunizing with Quil A ® or Poly I:C in combination with several antigens [22,51,52,53,54,55], supporting the aforementioned inter-species differences observed in vitro. In this regard, S. suis enolase formulated with Quil A ® triggered a balanced type 1/type2 profile in mice [12].…”

Section: Discussionmentioning

confidence: 91%

Porcine Dendritic Cells as an In Vitro Model to Assess the Immunological Behaviour of Streptococcus suis Subunit Vaccine Formulations and the Polarizing Effect of Adjuvants

et al. 2017

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An in vitro porcine bone marrow-derived dendritic cell (DC) culture was developed as a model for evaluating immune polarization induced by adjuvants when administered with immunogens that may become vaccine candidates if appropriately formulated. The swine pathogen Streptococcus suis was chosen as a prototype to evaluate proposed S. suis vaccine candidates in combination with the adjuvants Poly I:C, Quil A ®, Alhydrogel ®, TiterMax Gold ® and Stimune ®. The toll-like receptor ligand Poly I:C and the saponin Quil A ® polarized swine DC cytokines towards a type 1 phenotype, with preferential production of IL-12 and TNF-α. The water-in-oil adjuvants TiterMax Gold ® and Stimune ® favoured a type 2 profile as suggested by a marked IL-6 release. In contrast, Alhydrogel ® induced a type 1/type 2 mixed cytokine profile. The antigen type differently modified the magnitude of the adjuvant effect, but overall polarization was preserved. This is the first comparative report on swine DC immune activation by different adjuvants. Although further swine immunization studies would be required to better characterize the induced responses, the herein proposed in vitro model is a promising approach that helps assessing behaviour of the vaccine formulation rapidly at the pre-screening stage and will certainly reduce numbers of animals used while advancing vaccinology science.

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“…TLR ligands such as poly I:C are promising tools to induce antitumor immunity by increasing IL‐12 production and maturation of DC in vivo . However, it has been reported that the TLR3/TRIF/MyD88‐NF‐kb signaling pathway in DC generally induces IL‐6 as well as IL‐12 . Therefore, we speculate that the IL‐6‐deficient condition promotes the antitumor effect of immunoadjuvant therapy using poly I:C.…”

Section: Future Perspectivementioning

confidence: 88%

Interleukin‐6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

et al. 2017

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Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)‐6, a pleiotropic cytokine, is highly produced in the tumor‐bearing host. Previous studies have indicated that IL‐6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL‐6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD11b+ CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL‐6 gene, downregulated surface expression of human leukocyte antigen (HLA)‐DR, and an attenuated T cell‐stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL‐6‐mediated STAT3 activation reduced surface expression of HLA‐DR on CD14+ monocyte‐derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL‐6‐mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL‐6‐mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL‐6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

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Synergy of TLR3 and 7 ligands significantly enhances function of DCs to present inactivated PRRSV antigen through TRIF/MyD88-NF-κB signaling pathway

Cited by 29 publications

References 55 publications

Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

Porcine Dendritic Cells as an In Vitro Model to Assess the Immunological Behaviour of Streptococcus suis Subunit Vaccine Formulations and the Polarizing Effect of Adjuvants

Interleukin‐6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

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