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Glutamine antagonist JHU083 reprograms immunosuppressive tumor-associated macrophages to drive tumor immunity in urologic cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE230162 | GEO | 2024/05/17

REPOSITORIES: GEO

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Glutamine antagonist JHU083 reprograms immunosuppressive tumor-associated macrophages to drive tumor immunity in urologic cancers, bulk RNA-seq

Project description: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.

2024-05-18 | GSE229222 | GEO

Glutamine antagonist JHU083 reprograms immunosuppressive tumor-associated macrophages to drive tumor immunity in urologic cancers, single-cell RNA-seq

2024-05-18 | GSE229223 | GEO

RNA-sequencing on sorted tumor-associated macrophages from vehicle or JHU083 pro-drug of 6-Diazo-5-oxo-L-norleucine (glutamine antagonist) treated 4T1 (breast cancer) tumor bearing mice

Project description:RNA-sequencing was performed on sorted tumor-associated macrophages (CD45+7AAD-CD11b+F4/80+CD8-Ly6C-Ly6G-) from 4T1 tumor (murine breast cancer) bearig mice with or without JHU083, pro-drug of 6-Diazo-5-oxo-L-norleucine (glutamine antagonist) treatment for expression profiling

2020-07-08 | GSE119733 | GEO