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GSE85044
Mus musculus
16 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the nature and dynamics of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogenous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs emerge as clinically relevant parameters in lung cancer. In this study we used an orthotopic preclinical model of lung cancer to interrogate the transcriptome of lung tumor-infiltrating DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b+ cells which, compared to peritumoral lung DC counterparts, strongly over-express the T cell inhibitory molecule PD-L1 and acquire classic markers of tumor-supporting macrophages (TAM) on their surface. Transcriptome analysis of these CD11b+ tumor-infiltrating DCs (TIDCs) indicates impaired anti-tumoral immunogenicity, confirms the skewing towards TAM-related features, and indicates exposure to a hypoxic environment. In paralled, TIDCs display a specific micro-RNA signature dominated by the prototypical lung cancer oncomir miR-31. Hypoxia was found to drive intrinsic miR-31 expression in CD11b+DCs. Conditioned medium of mir-31-overexpressing CD11b+DCs induces pro-invasive lung cancer cell shape changes and is enriched with the pro-metastatic factors S100A8 and S100A9. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which lung cancer co-opts the plasticity of the DC system to support tumoral progression. Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the nature and dynamics of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogenous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs emerge as clinically relevant parameters in lung cancer. In this study we used an orthotopic preclinical model of lung cancer to interrogate the transcriptome of lung tumor-infiltrating DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b+ cells which, compared to peritumoral lung DC counterparts, strongly over-express the T cell inhibitory molecule PD-L1 and acquire classic markers of tumor-supporting macrophages (TAM) on their surface. Transcriptome analysis of these CD11b+ tumor-infiltrating DCs (TIDCs) indicates impaired anti-tumoral immunogenicity, confirms the skewing towards TAM-related features, and indicates exposure to a hypoxic environment. In paralled, TIDCs display a specific micro-RNA signature dominated by the prototypical lung cancer oncomir miR-31. Hypoxia was found to drive intrinsic miR-31 expression in CD11b+DCs. Conditioned medium of mir-31-overexpressing CD11b+DCs induces pro-invasive lung cancer cell shape changes and is enriched with the pro-metastatic factors S100A8 and S100A9. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which lung cancer co-opts the plasticity of the DC system to support tumoral progression.
Publication Title
The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 17 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 17 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been studied extensively in model organisms, little is known about these first responders in humans, especially their lineage and functional kinships to cytokine-secreting T helper cell (Th) counterparts. Here, we report gene regulatory circuitries for four human ILCTh counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells, but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell identity genes in each lineage, uncovering new modes of regulation for signature cytokines, novel molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILCTh subsets.
Publication Title
Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st), Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st), Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Most B cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC-B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions transcriptional circuits from normal GC-B cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression is deregulated in FL, target commandeered versus decommissioned REs. Our approach reveals two distinct subtypes of low-grade FL, whose pathogenic circuitries resemble GC-B or activated B cells. Remarkably, FL-altered enhancers also are enriched for sequence variants, including somatic mutations, which disrupt transcription factor binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC-B transformation.
Publication Title
Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples