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| Status |
Public on Mar 04, 2021 |
| Title |
Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas [scRNA-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
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| Overall design |
GL261 glioma cell lines episomally expressing wildtype or R132H-mutated Isocitrate Dehydrogenase 1 were injected intracerebrally into C57Bl6/J mice. After 7 or 28 days mice were sacrificed and cells were FACS-sorted on CD45. Single-cell RNA-Seq libraries were prepared using the 10x Single Cell 3' v2 Kit.
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| Contributor(s) |
Sankowski R, Friedrich M, Bunse L, Prinz M, Platten M |
| Citation(s) |
35609569 |
| |
| Submission date |
Feb 04, 2021 |
| Last update date |
Jun 01, 2023 |
| Contact name |
Roman Sankowski |
| E-mail(s) |
roman.sankowski@uniklinik-freiburg.de
|
| Phone |
+4976127051110
|
| Organization name |
University of Freiburg Medical Center
|
| Department |
Institute of Neuropathology
|
| Lab |
Prinz Lab
|
| Street address |
Breisacher Str. 64
|
| City |
Freiburg |
| ZIP/Postal code |
79106 |
| Country |
Germany |
| |
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| Platforms (2) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (64)
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| This SubSeries is part of SuperSeries: |
| GSE166420 |
Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas |
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| Relations |
| BioProject |
PRJNA699601 |
| SRA |
SRP304784 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE166218_014962_late_barcodes.tsv.gz |
28.2 Kb |
(ftp)(http) |
TSV |
| GSE166218_014962_late_features.tsv.gz |
272.8 Kb |
(ftp)(http) |
TSV |
| GSE166218_014962_late_info.h5 |
162.5 Mb |
(ftp)(http) |
H5 |
| GSE166218_014962_late_matrix.mtx.gz |
33.9 Mb |
(ftp)(http) |
MTX |
| GSE166218_Mm_CD45_IDH_SMAR_6mice_aggregation.csv.gz |
215 b |
(ftp)(http) |
CSV |
| GSE166218_Mm_CD45_IDH_SMAR_6mice_filtered_feature_bc_matrix.h5 |
26.2 Mb |
(ftp)(http) |
H5 |
| GSE166218_Mm_CD45_IDH_SMAR_6mice_raw_feature_bc_matrix.h5 |
115.5 Mb |
(ftp)(http) |
H5 |
| GSE166218_Mm_CD45_IDH_SMAR_6mice_summary.json.gz |
1013 b |
(ftp)(http) |
JSON |
| GSE166218_Mm_CD45_IDH_SMAR_6mice_web_summary.html.gz |
2.1 Mb |
(ftp)(http) |
HTML |
| GSE166218_ea_RH_1_v3_filtered_feature_bc_matrix.h5 |
14.8 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_1_v3_metrics_summary.csv.gz |
365 b |
(ftp)(http) |
CSV |
| GSE166218_ea_RH_1_v3_molecule_info.h5 |
171.9 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_1_v3_raw_feature_bc_matrix.h5 |
39.1 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_2_v3_filtered_feature_bc_matrix.h5 |
15.9 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_2_v3_metrics_summary.csv.gz |
368 b |
(ftp)(http) |
CSV |
| GSE166218_ea_RH_2_v3_molecule_info.h5 |
180.2 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_2_v3_raw_feature_bc_matrix.h5 |
40.3 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_3_v3_filtered_feature_bc_matrix.h5 |
12.8 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_3_v3_metrics_summary.csv.gz |
363 b |
(ftp)(http) |
CSV |
| GSE166218_ea_RH_3_v3_molecule_info.h5 |
144.3 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_3_v3_raw_feature_bc_matrix.h5 |
33.1 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_4_v3_filtered_feature_bc_matrix.h5 |
24.5 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_4_v3_metrics_summary.csv.gz |
369 b |
(ftp)(http) |
CSV |
| GSE166218_ea_RH_4_v3_molecule_info.h5 |
260.8 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_RH_4_v3_raw_feature_bc_matrix.h5 |
48.9 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_1_v3_filtered_feature_bc_matrix.h5 |
20.2 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_1_v3_metrics_summary.csv.gz |
361 b |
(ftp)(http) |
CSV |
| GSE166218_ea_WT_1_v3_molecule_info.h5 |
213.0 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_1_v3_raw_feature_bc_matrix.h5 |
42.8 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_2_v3_filtered_feature_bc_matrix.h5 |
53.5 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_2_v3_metrics_summary.csv.gz |
365 b |
(ftp)(http) |
CSV |
| GSE166218_ea_WT_2_v3_molecule_info.h5 |
260.5 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_2_v3_raw_feature_bc_matrix.h5 |
66.8 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_3_v3_filtered_feature_bc_matrix.h5 |
24.5 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_3_v3_metrics_summary.csv.gz |
368 b |
(ftp)(http) |
CSV |
| GSE166218_ea_WT_3_v3_molecule_info.h5 |
292.3 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_3_v3_raw_feature_bc_matrix.h5 |
51.7 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_4_v3_filtered_feature_bc_matrix.h5 |
18.6 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_4_v3_metrics_summary.csv.gz |
366 b |
(ftp)(http) |
CSV |
| GSE166218_ea_WT_4_v3_molecule_info.h5 |
233.4 Mb |
(ftp)(http) |
H5 |
| GSE166218_ea_WT_4_v3_raw_feature_bc_matrix.h5 |
45.1 Mb |
(ftp)(http) |
H5 |
| GSE166218_metadata.csv.gz |
2.1 Mb |
(ftp)(http) |
CSV |
| GSE166218_raw_counts.RData.gz |
165.6 Mb |
(ftp)(http) |
RDATA |
| GSE166218_scaled_counts.RData.gz |
161.1 Mb |
(ftp)(http) |
RDATA |
| GSE166218_seurat-integration-10x-wt-rh-gbm.RData.gz |
1.5 Gb |
(ftp)(http) |
RDATA |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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