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GEO help: Mouse over screen elements for information. |
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| Status |
Public on May 18, 2024 |
| Title |
Glutamine antagonist JHU083 reprograms immunosuppressive tumor-associated macrophages to drive tumor immunity in urologic cancers, bulk RNA-seq |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Glutamine metabolism in the tumor microenvironment is emerging as a critical regulator of immune-mediated anti-tumor responses. We report potent tumor growth inhibition by the glutamine antagonist prodrug JHU083 in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). Using orthogonal approaches, we show that JHU083-mediated glutamine antagonism in the tumor microenvironment induces TNF, inflammatory, and mTORC1 signaling in different intra-tumoral TAM clusters. Additionally, we report that JHU083 increases proliferation in tissue-resident macrophages intratumorally and in different TAM sub-clusters. Functionally, we report that JHU083-reprogrammed TAMs have increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of glutamine consumption in TAMs results in increased glycolysis, broken TCA cycle, and disruption in purine metabolism. Although the effect of glutamine antagonism was less profound on tumor-infiltrating T cells for their anti-tumor activity, it promoted a stem cell-like phenotype in CD8+ T cells and decreased the CD4+ Treg abundance. Additionally, we report that JHU083 causes a global shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumoral features.
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| Overall design |
Subcutaneous B6CaP tumors were harvested from mice treated with JHU083 or control. Tumors were dissociated and macrophages were fluorescence-activated cell sorted (FACS) by CD45+CD3-Ly6G-CD11b-F4/80+ and submitted for bulk RNA-sequencing.
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| Contributor(s) |
Lee AJ |
| Citation(s) |
38701369 |
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| Submission date |
Apr 07, 2023 |
| Last update date |
Aug 17, 2024 |
| Contact name |
Alex Jea-Eun Lee |
| E-mail(s) |
alee262@jhmi.edu
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| Organization name |
Johns Hopkins University
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| Street address |
1650 Orleans Street
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| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21231 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (12)
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| GSM7157132 |
Control, TAMs, mouse 959 |
| GSM7157133 |
Control, TAMs, mouse 961 |
| GSM7157134 |
Control, TAMs, mouse 962 |
| GSM7157135 |
JHU083, TAMs, mouse 955 |
| GSM7157136 |
JHU083, TAMs, mouse 956 |
| GSM7157137 |
JHU083, TAMs, mouse 957 |
| GSM7157138 |
JHU083, TAMs, mouse 958 |
| GSM7157139 |
JHU083, TAMs, mouse 963 |
| GSM7157140 |
JHU083, TAMs, mouse 964 |
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| This SubSeries is part of SuperSeries: |
| GSE230162 |
Glutamine antagonist JHU083 reprograms immunosuppressive tumor-associated macrophages to drive tumor immunity in urologic cancer |
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| Relations |
| BioProject |
PRJNA953423 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE229222_JHU083_treated_vs_Control_genes_DESeq2.txt.gz |
561.5 Kb |
(ftp)(http) |
TXT |
| GSE229222_RAW.tar |
15.4 Mb |
(http)(custom) |
TAR (of RESULTS) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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