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TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo.

ABSTRACT: Plasmacytoid dendritic cells (pDCs) are a unique subset of naturally occurring dendritic cells, which triggers the production of large amounts of type I interferons (IFNs) after viral infections through Toll-like receptor (TLR) 7 and TLR9. Recent studies have demonstrated that the activation of pDCs kills melanoma cells. However, the role of activated pDCs in breast cancer remains to be determined. In the present study, we generated mouse models of breast cancer and demonstrated that activated pDCs can directly kill breast tumor cells through TRAIL and Granzyme B. Furthermore, we established that pDCs initiate the sequential activation of NK cells and CD8+ T cells, and ultimately inhibit breast tumor growth. Understanding the role of activated pDCs in breast cancer may help to develop new strategies for manipulating the function of pDCs and induce anti-tumor immunity in breast cancer.

SUBMITTER: Wu J

PROVIDER: S-EPMC5355297 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo.

Wu Jing J Li Shuang S Yang Yang Y Zhu Shan S Zhang Mingyou M Qiao Yuan Y Liu Yong-Jun YJ Chen Jingtao J

Oncotarget 20170201 7

Plasmacytoid dendritic cells (pDCs) are a unique subset of naturally occurring dendritic cells, which triggers the production of large amounts of type I interferons (IFNs) after viral infections through Toll-like receptor (TLR) 7 and TLR9. Recent studies have demonstrated that the activation of pDCs kills melanoma cells. However, the role of activated pDCs in breast cancer remains to be determined. In the present study, we generated mouse models of breast cancer and demonstrated that activated p ...[more]

PMID: 28052019

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Project description:BackgroundPlasmacytoid Dendritic Cells (pDC) comprise approximately 0.2 to 0.8% of the blood mononuclear cells and are the primary type 1 interferon (IFN), producing cells, secreting high levels of IFN in response to viral infections. Plasmacytoid dendritic cells express predominantly TLRs 7 & 9, making them responsive to ssRNA and CpG DNA. The objective of this study was to evaluate the molecular and cellular processes altered upon stimulation of pDC with synthetic TLR 7 and TLR 7/8 agonists. To this end, we evaluated changes in global gene expression upon stimulation of 99.9% pure human pDC with the TLR7 selective agonists 3M-852A, and the TLR7/8 agonist 3M-011.ResultsGlobal gene expression was evaluated using the Affymetrix U133A GeneChip(R) and selected genes were confirmed using real time TaqMan(R) RTPCR. The gene expression profiles of the two agonists were similar indicating that changes in gene expression were solely due to stimulation through TLR7. Type 1 interferons were among the highest induced genes and included IFNB and multiple IFNalpha subtypes, IFNalpha2, alpha5, alpha6, alpha8, alpha1/13, alpha10, alpha14, alpha16, alpha17, alpha21. A large number of chemokines and co-stimulatory molecules as well as the chemokine receptor CCR7 were increased in expression indicating maturation and change in the migratory ability of pDC. Induction of an antiviral state was shown by the expression of several IFN-inducible genes with known anti-viral activity. Further analysis of the data using the pathway analysis tool MetaCore gave insight into molecular and cellular processes impacted. The analysis revealed transcription networks that show increased expression of signaling components in TLR7 and TLR3 pathways, and the cytosolic anti-viral pathway regulated by RIG1 and MDA5, suggestive of optimization of an antiviral state targeted towards RNA viruses. The analysis also revealed increased expression of a network of genes important for protein ISGylation as well as an anti-apoptotic and pro-survival gene expression program.ConclusionThus this study demonstrates that as early as 4 hr post stimulation, synthetic TLR7 agonists induce a complex transcription network responsible for activating pDC for innate anti-viral immune responses with optimized responses towards RNA viruses, increased co-stimulatory capacity, and increased survival.

Project description:BackgroundTranscription factors (TFs) control gene expression by direct binding to regulatory regions of target genes but also by impacting chromatin landscapes and modulating DNA accessibility for other TFs. In recent years several TFs have been defined that control cell fate decisions and effector functions in the immune system. Plasmacytoid dendritic cells (pDCs) are an immune cell type with the unique capacity to produce high amounts of type I interferons quickly in response to contact with viral components. Hereby, this cell type is involved in anti-infectious immune responses but also in the development of inflammatory and autoimmune diseases. To date, the global TF reservoir in pDCs early after activation remains to be fully characterized.ResultsTo fill this gap, we have performed a comprehensive analysis in naïve versus TLR9-activated murine pDCs in a time course study covering early timepoints after stimulation (2 h, 6 h, 12 h) integrating gene expression (RNA-Seq) and chromatin landscape (ATAC-Seq) studies. To unravel the biological processes underlying the changes in TF expression on a global scale gene ontology (GO) analyses were performed. We found that 70% of all genes annotated as TFs in the mouse genome (1014 out of 1636) are expressed in pDCs for at least one stimulation time point and are covering a wide range of TF classes defined by their specific DNA binding mechanisms. GO analysis revealed involvement of TLR9-induced TFs in epigenetic modulation, NFκB and JAK-STAT signaling, and protein production in the endoplasmic reticulum. pDC activation predominantly "turned on" the chromatin regions associated with TF genes. Our in silico analyses pointed at the AP-1 family of TFs as less noticed but possibly important players in these cells after activation. AP-1 family members exhibit (1) increased gene expression, (2) enhanced chromatin accessibility in their promoter region, and (3) a TF DNA binding motif that is globally enriched in genomic regions that were found more accessible in pDCs after TLR9 activation.ConclusionsIn this study we define the complete set of TLR9-regulated TFs in pDCs. Further, this study identifies the AP-1 family of TFs as potentially important but so far less well characterized regulators of pDC function.

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TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo.

Publications

TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo.

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