Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas [CEL-Seq2]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA700854 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13665211_1.fastq.gz | Fastqsanger.gz | |||
| SRR13665211_2.fastq.gz | Fastqsanger.gz | |||
| SRR13665212_1.fastq.gz | Fastqsanger.gz | |||
| SRR13665212_2.fastq.gz | Fastqsanger.gz | |||
| SRR13665213_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 104 |
Similar Datasets
Project description:Intratumoral microglia and MΦ constitute up to 70% of the tumor mass of high-grade gliomas (HGG) with profound impact on hallmarks of malignancy such as angiogenesis and immunosuppression. The dynamics and functional states of intratumoral myeloid cells during tumor progression and the molecular mechanisms controlling them are poorly understood. Here we define homeostatic and antigen-presenting myeloid cellular states in experimental and human HGG by longitudinal single-cell RNA-sequencing and combined transcriptome and proteome profiling, respectively. During glioma progression, myeloid cells gradually shift from a homeostatic to a tumor-associated effector state. We show that these dynamics are under strict control by early changes in resident microglia and the tumor genotype: In gliomas with mutations in isocitrate dehydrogenase (IDH), a disease-defining driver mutation, differentiation of invaded myeloid cells was blocked resulting in an immature, immunosuppressive phenotype. In late-stage IDH-mutant gliomas, monocyte-derived MΦ drive a tolerogenic remodeling of the glioma microenvironment thus preventing T-cell response. We define the molecular mechanism responsible for blocking functional differentiation in IDH-mutant gliomas to be causally related to enhanced metabolization of tryptophan to kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AHR), leading to a time-dependent uptake of extracellular tryptophan via LAT1-CD98 by intratumoral myeloid cells. Consequently, the immunosuppressive phenotype in IDH-mutant glioma models was reversed by pharmacologic inhibition of LAT1-CD98 or AHR. Thus, we provide evidence for a tumor genotype-dependent dynamic network of resident and recruited intratumoral myeloid cells shaping the immune microenvironment of IDH-mutant HGG and identify tryptophan metabolism as a viable therapeutic target for the immunotherapy of IDH-mutant tumors.
2021-03-04 | GSE166418 | GEO
Project description:Intratumoral microglia and MΦ constitute up to 70% of the tumor mass of high-grade gliomas (HGG) with profound impact on hallmarks of malignancy such as angiogenesis and immunosuppression. The dynamics and functional states of intratumoral myeloid cells during tumor progression and the molecular mechanisms controlling them are poorly understood. Here we define homeostatic and antigen-presenting myeloid cellular states in experimental and human HGG by longitudinal single-cell RNA-sequencing and combined transcriptome and proteome profiling. During glioma progression, myeloid cells gradually shift from a homeostatic to a tumor-associated effector state. We show that these dynamics are under strict control by early changes in resident microglia and the tumor genotype: In gliomas with mutations in isocitrate dehydrogenase (IDH), a disease-defining driver mutation, differentiation of invaded myeloid cells was blocked resulting in an immature, immunosuppressive phenotype. In late-stage IDH-mutant gliomas, monocyte-derived MΦ drive a tolerogenic remodeling of the glioma microenvironment thus preventing T-cell response. We define the molecular mechanism responsible for the tumor genotype-dependent education of infiltrating MΦ to be causally related to an enzymatically enhanced tryptophan catabolism via TDO2, resulting in the production of kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AHR). TDO2 activation further induces an amino acid starvation response triggering the import of exogenous tryptophan by intratumoral MΦ via LAT1-CD98. We here provide evidence that paracrine R-2-HG and tryptophan are critically involved in the differentiation and activation of monocyte-derived MΦ and that the previously observed altered amino acid metabolism in IDHmut gliomas is also responsible for shaping an immunosuppressive tumor microenvironment through maintenance of this complex metabolic axis. We further show that this regulatory metabolic network is particularly active in infiltrating MΦ because of their distinct expression profile that constitutes an immune subset-specific metabolic vulnerability. Consequently, the immunosuppressive phenotype in IDH-mutant glioma models was reversed by pharmacological inhibition of LAT1-CD98 or AHR. Thus, we provide evidence for a tumor genotype-dependent, dynamic network of resident and recruited intratumoral myeloid cells that shape the immune microenvironment of IDH-mutant HGG through pleiotropic interaction with the tumor metabolome and identify tryptophan metabolism as a viable therapeutic target for the immunotherapy of IDH-mutant tumors.
2021-03-04 | GSE166521 | GEO
Project description:Intratumoral microglia and MΦ constitute up to 70% of the tumor mass of high-grade gliomas (HGG) with profound impact on hallmarks of malignancy such as angiogenesis and immunosuppression. The dynamics and functional states of intratumoral myeloid cells during tumor progression and the molecular mechanisms controlling them are poorly understood. Here we define homeostatic and antigen-presenting myeloid cellular states in experimental and human HGG by longitudinal single-cell RNA-sequencing and combined transcriptome and proteome profiling. During glioma progression, myeloid cells gradually shift from a homeostatic to a tumor-associated effector state. We show that these dynamics are under strict control by early changes in resident microglia and the tumor genotype: In gliomas with mutations in isocitrate dehydrogenase (IDH), a disease-defining driver mutation, differentiation of invaded myeloid cells was blocked resulting in an immature, immunosuppressive phenotype. In late-stage IDH-mutant gliomas, monocyte-derived MΦ drive a tolerogenic remodeling of the glioma microenvironment thus preventing T-cell response. We define the molecular mechanism responsible for the tumor genotype-dependent education of infiltrating MΦ to be causally related to an enzymatically enhanced tryptophan catabolism via TDO2, resulting in the production of kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AHR). TDO2 activation further induces an amino acid starvation response triggering the import of exogenous tryptophan by intratumoral MΦ via LAT1-CD98. We here provide evidence that paracrine R-2-HG and tryptophan are critically involved in the differentiation and activation of monocyte-derived MΦ and that the previously observed altered amino acid metabolism in IDHmut gliomas is also responsible for shaping an immunosuppressive tumor microenvironment through maintenance of this complex metabolic axis. We further show that this regulatory metabolic network is particularly active in infiltrating MΦ because of their distinct expression profile that constitutes an immune subset-specific metabolic vulnerability. Consequently, the immunosuppressive phenotype in IDH-mutant glioma models was reversed by pharmacological inhibition of LAT1-CD98 or AHR. Thus, we provide evidence for a tumor genotype-dependent, dynamic network of resident and recruited intratumoral myeloid cells that shape the immune microenvironment of IDH-mutant HGG through pleiotropic interaction with the tumor metabolome and identify tryptophan metabolism as a viable therapeutic target for the immunotherapy of IDH-mutant tumors.
2021-03-04 | GSE166218 | GEO
Project description:Single-cell transcriptomics requires a method that is sensitive, accurate, and reproducible. Here, we present CEL-Seq2, a modified version of our CEL-Seq method, with three-fold higher sensitivity, lower costs, and less hands-on time. We also implemented CEL-Seq2 on Fluidigm’s C1 system, thereby providing its first single-cell, on-chip barcoding method, and detected gene expression changes accompanying the progression through the cell cycle in mouse fibroblast cells. We also compare with Smart-Seq to demonstrate CEL-Seq2’s increased sensitivity relative to other available methods. Collectively, the improvements make CEL-Seq2 uniquely suited to single-cell RNA-Seq analysis in terms of economics, resolution, and ease of use
2016-04-08 | GSE78779 | GEO
Project description:Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas
| PRJNA700856 | ENA
Project description:Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas [RNA-Seq]
| PRJNA701180 | ENA
Project description:Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas [scRNA-Seq]
| PRJNA699601 | ENA
Project description:Gene expression in mouse blood cells from sorted via FACS analysis into a 384-well plate were profiled using a modified CEL-seq2 protocol.
2018-02-28 | GSE109999 | GEO
Project description:CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq
| PRJNA313513 | ENA
Project description:Single cell profiling of mouse blood cells using CEL-seq2
| PRJNA432538 | ENA