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. 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, 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 | GSE166218 | 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 [scRNA-Seq]
| PRJNA699601 | ENA
Project description:Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas [CEL-Seq2]
| PRJNA700854 | ENA
Project description:Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas [RNA-Seq]
| PRJNA701180 | ENA
Project description:The immune microenvironment is important for the development, progression, and prognosis of anaplastic glioma (AG). This complex milieu has not been fully elucidated, and a high-dimensional analysis is urgently required. Utilizing mass cytometry (CyTOF), we performed an analysis of immune cells from 5 patients with anaplastic astrocytoma, IDH-mutant (AAmut) and 10 patients with anaplastic oligodendroglioma, IDH-mutant and 1p/19q codeletion (AOD) and their paired peripheral blood mononuclear cells (PBMCs). Based on a panel of 33 biomarkers, we demonstrated the tumor-driven immune changes in the AG immune microenvironment. Our study confirmed that mononuclear phagocytes and T cells are the most abundant immunocytes in the AG immune microenvironment. Glioma-associated microglia/macrophages in both AAmut and AOD samples showed highly immunosuppressive characteristics. Compared to those in the PBMCs, the ratios of immune checkpoint-positive exhausted CD4+ T cells and CD8+ T cells were higher at the AG tumor sites. The AAmut immune milieu exhibits more immunosuppressive characteristics than that in AOD.
| S-EPMC7890006 | biostudies-literature
Project description:BackgroundRoughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that IDH-mutant gliomas share a common developmental hierarchy. However, the neural lineages and differentiation stages in IDH-mutant gliomas remain inadequately characterized.MethodsUsing bulk transcriptomes and single-cell transcriptomes, we identified genes enriched in IDH-mutant gliomas with or without 1p19q co-deletion, we also assessed the expression pattern of stage-specific signatures and key regulators of oligodendrocyte lineage differentiation. We compared the expression of oligodendrocyte lineage stage-specific markers between quiescent and proliferating malignant single cells. The gene expression profiles were validated using RNAscope analysis and myelin staining and were further substantiated using data of DNA methylation and single-cell ATAC-seq. As a control, we assessed the expression pattern of astrocyte lineage markers.ResultsGenes concordantly enriched in both subtypes of IDH-mutant gliomas are upregulated in oligodendrocyte progenitor cells (OPC). Signatures of early stages of oligodendrocyte lineage and key regulators of OPC specification and maintenance are enriched in all IDH-mutant gliomas. In contrast, signature of myelin-forming oligodendrocytes, myelination regulators, and myelin components are significantly down-regulated or absent in IDH-mutant gliomas. Further, single-cell transcriptomes of IDH-mutant gliomas are similar to OPC and differentiation-committed oligodendrocyte progenitors, but not to myelinating oligodendrocyte. Most IDH-mutant glioma cells are quiescent; quiescent cells and proliferating cells resemble the same differentiation stage of oligodendrocyte lineage. Mirroring the gene expression profiles along the oligodendrocyte lineage, analyses of DNA methylation and single-cell ATAC-seq data demonstrate that genes of myelination regulators and myelin components are hypermethylated and show inaccessible chromatin status, whereas regulators of OPC specification and maintenance are hypomethylated and show open chromatin status. Markers of astrocyte precursors are not enriched in IDH-mutant gliomas.ConclusionsOur studies show that despite differences in clinical manifestation and genomic alterations, all IDH-mutant gliomas resemble early stages of oligodendrocyte lineage and are stalled in oligodendrocyte differentiation due to blocked myelination program. These findings provide a framework to accommodate biological features and therapy development for IDH-mutant gliomas.
| S-EPMC10103394 | biostudies-literature
Project description:Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.
| S-EPMC7995203 | biostudies-literature