Impaired activation of plasmacytoid dendritic cells via Toll-Like receptor 7/9 and STING is mediated by melanoma-derived immunosuppressive cytokines and metabolic drift.
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ABSTRACT:
PROVIDER: PRJNA981452 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR24874653.fastq.gz | Fastqsanger.gz | |||
| SRR24874654.fastq.gz | Fastqsanger.gz | |||
| SRR24874655.fastq.gz | Fastqsanger.gz | |||
| SRR24874656.fastq.gz | Fastqsanger.gz | |||
| SRR24874657.fastq.gz | Fastqsanger.gz |
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Project description:Plasmacytoid dendritic cells (pDCs) infiltrate a large set of human cancers. IFN-α produced by pDCs might induce growth arrest and apoptosis in tumor cells and modulates innate and adaptive immune cells involved in anti-cancer immunity. Moreover, pDC-derived effector molecules exert tumor cell killing. However, the activation state and clinical relevance of pDCs infiltration in cancer is still largely controversial. In Primary Cutaneous Melanoma (PCM), pDCs density decreases over disease progression and collapses in metastatic melanoma (MM). Moreover, the residual circulating pDC compartment is defective in IFN-α production. Here, based on a set of microscopic, functional and in silico analysis, we demonstrated that the melanoma secretome directly impairs type I interferon and CXCL10 production by pDCs via TLR-7/9 and cGAS-STING signaling pathways. As proposed byBased on bulk transcriptomic data, we could confirmed that TGF-β and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape.
2023-12-31 | GSE234446 | GEO
Project description:IntroductionPlasmacytoid dendritic cells (pDCs) infiltrate a large set of human cancers. Interferon alpha (IFN-α) produced by pDCs induces growth arrest and apoptosis in tumor cells and modulates innate and adaptive immune cells involved in anti-cancer immunity. Moreover, effector molecules exert tumor cell killing. However, the activation state and clinical relevance of pDCs infiltration in cancer is still largely controversial. In Primary Cutaneous Melanoma (PCM), pDCs density decreases over disease progression and collapses in metastatic melanoma (MM). Moreover, the residual circulating pDC compartment is defective in IFN-α production.MethodsThe activation of tumor-associated pDCs was evaluated by in silico and microscopic analysis. The expression of human myxovirus resistant protein 1 (MxA), as surrogate of IFN-α production, and proximity ligation assay (PLA) to test dsDNA-cGAS activation were performed on human melanoma biopsies. Moreover, IFN-α and CXCL10 production by in vitro stimulated (i.e. with R848, CpG-A, ADU-S100) pDCs exposed to melanoma cell lines supernatants (SN-mel) was tested by intracellular flow cytometry and ELISA. We also performed a bulk RNA-sequencing on SN-mel-exposed pDCs, resting or stimulated with R848. Glycolytic rate assay was performed on SN-mel-exposed pDCs using the Seahorse XFe24 Extracellular Flux Analyzer.ResultsBased on a set of microscopic, functional and in silico analyses, we demonstrated that the melanoma milieu directly impairs IFN-α and CXCL10 production by pDCs via TLR-7/9 and cGAS-STING signaling pathways. Melanoma-derived immunosuppressive cytokines and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape.DiscussionThese findings propose a new window of intervention for novel immunotherapy approaches to amplify the antitumor innate immune response in cutaneous melanoma (CM).
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Project description:GVHD-mediated Vicious Cascade: Impaired Reconstitution of Immunosuppressive Donor Plasmacytoid Dendritic Cells
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Project description:Many normal tissues undergo age-related DNA methylation drift providing a quantitative measure of tissue age. However this drift has not been demonstrated in neoplastic tissues. Here we identify and validate 781 CpG-islands (CGIs) that undergo significant methylomic drift in normal colorectal tissues continue to drift in neoplasia and remain significantly correlated with one another across tissue samples. However compared with normal colon this drift advances (~3-4 fold) faster in neoplasia consistent with increased cell proliferation during neoplastic progression. Furthermore we show that the observed drift patterns are broadly consistent with modeled adenoma-carcinoma sojourn time distributions from colorectal cancer (CRC) incidence data. These results support the hypothesis that beginning with the founder premalignant cell cancer precursors frequently sojourn for decades before turning into cancer which implies that the founder cell typically arises early in life. We estimate that at least 77-89% of the observed drift variance in distal and rectal tumors is explained by stochastic variability associated with neoplastic progression while only 55% of the variance is explained for proximal tumors. However >50% of identified gene-CGI pairs in the proximal colon that undergo drift are significantly and mainly negatively correlated with cancer gene expression suggesting that methylomic drift participates in the clonal evolution of CRCs. Significance: Methylomic drift advances in colorectal neoplasia consistent with extended sojourn time distributions explaining a significant fraction of epigenetic heterogeneity in CRCs. Importantly the estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing CRC incidence.
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Project description:Epigenetic alterations, particularly the DNA methylation (DNAm) drift, represent a conserved hallmark of aging across species, influencing biological processes and disease pathogenesis. Recent studies have characterized different DNAm drifts in mammalian aging, and observed, for some of them, a correlation with cell division or organismal lifestyle. However, the molecular mechanisms driving DNAm drifts during aging are still largely unknown. In this study, we identify and characterize a cancer-associated intestine-specific DNAm drift, that initiates in healthy intestinal stem cells with impaired iron homeostasis, propagating through crypt clonality and crypt fission mechanisms to neighboring cells. Experimental evidence using mouse models and intestinal organoids confirms the cell-intrinsic, non-mitotic nature of ACCA drift. Despite the observed heterogeneity at the CpG level confirming the stochastic component of the epigenetic aging, DNAm patterns at the gene level remain consistent, implicating functional relevance to biological processes such as cancer initiation. Mechanistically, ACCA drift is driven by an impaired TET enzyme activity due to dysregulated iron metabolism, linking cellular metabolism to epigenetic alterations. Insights into the interplay between ACCA drift and colorectal cancer (CRC) suggest a mechanistic basis for DNAm changes observed in CRC, potentially explaining the hypermethylation landscape observed in cancerous tissuess. This study enhances our understanding of epigenetic mechanisms in aging and disease, highlighting potential targets for prevention and early-diagnosis of age-related diseases like CRC.
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Project description:Plasmacytoid dendritic cells (pDCs) are ÒnaturalÓ interferon _ (IFN_)-producing cells. Despite their importance to antiviral defense, autoimmunity, and ischemic liver graft injury, because DC subsets are rare and heterogeneous, basic questions about liver pDC function and capacity to make cytokines remain unanswered. Previous investigations failed to consistently detect IFN_ mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFN_. We used a combination of molecular, biochemical, cytometric, and high-dimensional techniques to analyze DC frequencies/functions in liver and peripheral blood mononuclear cells (PBMCs) of hepatitis C virus (HCV)-infected patients, to examine correlations between DC function and gene expression of matched whole liver tissue and liver mononuclear cells (LMCs), and to determine if pDCs can produce multiple cytokines. T cells often produce multiple cytokines/chemokines but until recently technical limitations have precluded tests of polyfunctionality in individual pDCs. Mass cytometry (CyTOF) revealed that liver pDCs are the only LMC that produces detectable amounts of IFN_ in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFN_ (~2 million molecules of IFN_/cell/hour) and produced more IFN_ than PBMCs after stimulation, p=0.0001. LMCs secreted >14-fold more IFN_ than IFN_ in 4 hours. Liver pDC frequency positively correlated with whole liver expression of ÒIFN_-responseÓ pathway (R2=0.58, p=0.007) and Òmonocyte surfaceÓ signature (R2=0.54, p=0.01). Mass cytometry revealed that IFN_-producing pDCs were highly polyfunctional; >90% also made 2-4 additional cytokines/chemokines of our test set of 10. Liver BDCA1 DCs, but not BDCA3 DCs, were similarly polyfunctional. pDCs from a healthy liver were also polyfunctional. Our data show that liver pDCs retain the ability to make abundant IFN_ during chronic HCV infection and produce many other immune modulators. Polyfunctional liver pDCs are likely to be key drivers of inflammation and immune activation during chronic HCV infection.
2019-07-10 | GSE134041 | GEO
Project description:Plasmacytoid dendritic cells (pDCs) are ÒnaturalÓ interferon _ (IFN_)-producing cells. Despite their importance to antiviral defense, autoimmunity, and ischemic liver graft injury, because DC subsets are rare and heterogeneous, basic questions about liver pDC function and capacity to make cytokines remain unanswered. Previous investigations failed to consistently detect IFN_ mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFN_. We used a combination of molecular, biochemical, cytometric, and high-dimensional techniques to analyze DC frequencies/functions in liver and peripheral blood mononuclear cells (PBMCs) of hepatitis C virus (HCV)-infected patients, to examine correlations between DC function and gene expression of matched whole liver tissue and liver mononuclear cells (LMCs), and to determine if pDCs can produce multiple cytokines. T cells often produce multiple cytokines/chemokines but until recently technical limitations have precluded tests of polyfunctionality in individual pDCs. Mass cytometry (CyTOF) revealed that liver pDCs are the only LMC that produces detectable amounts of IFN_ in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFN_ (~2 million molecules of IFN_/cell/hour) and produced more IFN_ than PBMCs after stimulation, p=0.0001. LMCs secreted >14-fold more IFN_ than IFN_ in 4 hours. Liver pDC frequency positively correlated with whole liver expression of ÒIFN_-responseÓ pathway (R2=0.58, p=0.007) and Òmonocyte surfaceÓ signature (R2=0.54, p=0.01). Mass cytometry revealed that IFN_-producing pDCs were highly polyfunctional; >90% also made 2-4 additional cytokines/chemokines of our test set of 10. Liver BDCA1 DCs, but not BDCA3 DCs, were similarly polyfunctional. pDCs from a healthy liver were also polyfunctional. Our data show that liver pDCs retain the ability to make abundant IFN_ during chronic HCV infection and produce many other immune modulators. Polyfunctional liver pDCs are likely to be key drivers of inflammation and immune activation during chronic HCV infection.
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Project description:Individual liver plasmacytoid dendritic cells are capable of producing IFNa and multiple additional cytokines during chronic HCV infection
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