Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212712 | GEO | 2024/02/21
REPOSITORIES: GEO
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Project description:Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. Here, we observed that DCs initiated a distinct transcriptional program during antigen presentation. We utilized a network-based approach to screen for DC-targeting therapeutics. Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing DC-mediated antigen presentation, leading to better T cell activation.
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Project description:Dendritic cells (DCs) process and present self and foreign antigens to induce tolerance or immunity. In vitro models suggest that induction of immunity is controlled by regulating the presentation of antigen, but little is known about how DCs control antigen presentation in vivo. To examine antigen processing and presentation in vivo we specifically targeted antigens to the two major subsets of DCs using chimeric monoclonal antibodies. Unlike CD8+ DCs that express the cell surface protein CD205, CD8- DCs, which are positive for the 33D1 antigen, are specialized for presentation on MHC class II. This difference in antigen processing is intrinsic to the DC subsets and associated with increased expression of proteins associated with MHC processing. Experiment Overall Design: This study includes data from cell sort purified dendritic cells, B cells and CD4 and CD8 T cells. The genearray was performed to identify the transmembrane molecule recognized by the antibody 33D1. The antibody 33D1 binds specifically to CD8-CD11cHigh DCs in the spleen. Therfore the data set was reduced in this way that all molecules that are expressed either in CD8=CD11cHigh DCs, B cells and T cells were diminished of the CD8+CD11cHigh DC data set. This Genearray was also used to analyze MHC class I and MHC class II associated moelcules as the DC subsets differ in the antigen presentation. Each Series consists of 3 individuall samples
2008-06-14 | E-GEOD-6259 | biostudies-arrayexpress
Project description:Induction of an effective tumor immunity is a complex process that includes the appropriate presentation of the tumor antigens, activation of specific T cells, and the elimination of malignant cells. Potent and efficient T cell activation is dependent on multiple factors, such as timely expression of co-stimulatory molecules, the differentiation state of professional antigen presenting cells (e.g. dendritic cells; DCs), the functionality of the antigen processing and presentation machinery (APPM), and the repertoire of HLA class I and II-bound peptides (termed immunopeptidome) presented to T cells. So far, how molecular perturbations underlying DCs maturation and differentiation affect the in vivo cross-presented HLA class I and II immunopeptidomes is largely unknown. Yet, this knowledge is crucial for further development of DC-based immunotherapy approaches. We applied a state-of-the-art sensitive MS-based immunopeptidomics approach to characterize the naturally presented HLA-I and -II immunopeptidomes eluted from autologous immune cells having distinct functional and biological states including CD14+ monocytes, immature DC (ImmDC) and mature DC (MaDC) monocyte-derived DCs and naive or activated T and B cells. We revealed a presentation of significantly longer HLA peptides upon activation that is HLA allotype specific. This was apparent in the self-peptidome upon cell activation and in the context of presentation of exogenously loaded antigens. Importantly, a similar trend was also present in a large collection of immunogenic HLA-I epitopes from pathogens, suggesting that peptide length is an important feature with potential implications on the rational design of anti-cancer vaccines.
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Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity. Comparison of murine mannose receptor negative versus mannose receptor positive bone marrow-derived DCs
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Project description:Cross-presentation of tumor antigens by dendritic cells (DCs) is crucial to prime and (re-) stimulate CD8+ T cells. This process is important in initiating and maintaining an anti-tumor response. Here, we show that tumor presence of conventional type 1 DCs (cDC1), a subtype that excels in cross-presentation, correlates with response to neoadjuvant immune checkpoint blockade (ICB) in melanoma. This led us to hypothesize that patients failing to respond to ICB could benefit from enhanced cross-presentation of tumor antigens. We therefore established a cross-presentation assay to screen over 5,500 compounds for enhancers of DC cross-presentation using induced T cell proliferation as readout. We identified 145 enhancers, including AZD5582, an antagonist of inhibitor of apoptosis proteins (IAPs) cIAP1, cIAP2 and XIAP. AZD5582 treatment led to DC activation of the non-canonical nuclear factor kappa B (NF-kB) pathway, enhanced antigen import from endolysosomes into the cytosol and increased expression of genes involved in cross-presentation. Furthermore, it upregulated expression of CD80, CD86, MHC class II, CD70 and secretion of TNF by DCs. This enhanced DC activation and maturation program was observed also in tumor-bearing mice upon AZD5582 treatment, culminating into an increased frequency of systemic tumor antigen-specific CD8+ T cells. Our results merit further exploration of AZD5582 to increase antigen cross-presentation for improving the clinical benefit of ICB in unfavorable patients.
2023-03-23 | GSE217050 | GEO
Project description:Cross-presentation of tumor antigens by dendritic cells (DCs) is crucial to prime and (re-) stimulate CD8+ T cells. This process is important in initiating and maintaining an anti-tumor response. Here, we show that tumor presence of conventional type 1 DCs (cDC1), a subtype that excels in cross-presentation, correlates with response to neoadjuvant immune checkpoint blockade (ICB) in melanoma. This led us to hypothesize that patients failing to respond to ICB could benefit from enhanced cross-presentation of tumor antigens. We therefore established a cross-presentation assay to screen over 5,500 compounds for enhancers of DC cross-presentation using induced T cell proliferation as readout. We identified 145 enhancers, including AZD5582, an antagonist of inhibitor of apoptosis proteins (IAPs) cIAP1, cIAP2 and XIAP. AZD5582 treatment led to DC activation of the non-canonical nuclear factor kappa B (NF-kB) pathway, enhanced antigen import from endolysosomes into the cytosol and increased expression of genes involved in cross-presentation. Furthermore, it upregulated expression of CD80, CD86, MHC class II, CD70 and secretion of TNF by DCs. This enhanced DC activation and maturation program was observed also in tumor-bearing mice upon AZD5582 treatment, culminating into an increased frequency of systemic tumor antigen-specific CD8+ T cells. Our results merit further exploration of AZD5582 to increase antigen cross-presentation for improving the clinical benefit of ICB in unfavorable patients.
2023-03-23 | GSE217048 | GEO
Project description:Dendritic cells (DCs) process and present self and foreign antigens to induce tolerance or immunity. In vitro models suggest that induction of immunity is controlled by regulating the presentation of antigen, but little is known about how DCs control antigen presentation in vivo. To examine antigen processing and presentation in vivo we specifically targeted antigens to the two major subsets of DCs using chimeric monoclonal antibodies. Unlike CD8+ DCs that express the cell surface protein CD205, CD8- DCs, which are positive for the 33D1 antigen, are specialized for presentation on MHC class II. This difference in antigen processing is intrinsic to the DC subsets and associated with increased expression of proteins associated with MHC processing. Keywords: cell type comparison of wildtype and Flt3L melonom spleen DCs and splenic B cells, CD4 and CD8 T cells
2006-12-01 | GSE6259 | GEO
Project description:Dendritic cells (DCs) are professional phagocytes that use innate sensing and phagocytosis to internalize and degrade self as well as foreign material, such as pathogenic bacteria, within phagosomes. These intracellular compartments are equipped to generate antigenic peptides that serve as source for antigen presentation to T cells initiating adaptive immune responses. Nonetheless, the phagosomal proteome of DCs is only partially studied, in particular in response to inflammatory cues. The phagosomal proteome is highly dynamic as it changes during phagosome maturation, when phagosomes sequentially interact with endosomes and lysosomes. In addition, the activation status of the phagocyte can modulate the phagosomal composition and is able to shape phagosomal functions. In this study, we determined spatiotemporal changes of the proteome of DC phagosomes during their maturation and compared resting and lipopolysaccharide (LPS)-stimulated bone marrow-derived DCs by label-free, quantitative mass spectrometry. Ovalbumin-coupled latex beads were used as phagocytosis model system and revealed that LPS-treated DCs show decreased recruitment of proteins involved in phagosome maturation, such as subunits of the vacuolar proton ATPase, cathepsin B, D, S and RAB7. In contrast, those phagosomes were characterized by an increased recruitment of proteins involved in antigen cross-presentation, e.g. different subunits of the proteasome and MHC I molecules, tapasin etc., confirming increased antigen presentation efficacy in those cells. In addition, we identified several phagosomal proteins that were not previously associated with phagosomal functions and reveal a novel role for immune-responsive gene 1 (IRG1) in phagocytic uptake of particles in resting DCs.
2019-02-28 | PXD012155 | Pride
Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity.
2009-06-19 | GSE15616 | GEO
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2021-02-10 | GSE162361 | GEO