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

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

PROVIDER: PRJNA957765 | ENA |

REPOSITORIES: ENA

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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

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

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

| PRJNA953423 | ENA

RNA-sequencing on sorted infiltrating CD8 T cells from vehicle or JHU083, pro-drug of 6-Diazo-5-oxo-L-norleucine (glutamine antagonist) treated MC38 (colon cancer) tumor bearing mice

Project description:RNA-sequencing was performed on sorted CD11b-CD11c-B220-CD45+TCRbeta+CD44+CD8+ TIL from vehicle or JHU083 treated MC38 tumor-bearing mice with or without JHU083, pro-drug of 6-Diazo-5-oxo-L-norleucine (glutamine antagonist) treatment for expression profiling

2020-02-24 | GSE120345 | GEO

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

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

| PRJNA953426 | ENA

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

Combined with Gefitinib Overcomes Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer

Project description:Glutamine is a major energy source for tumor cells and blocking glutamine metabolism is being investigated as a promising strategy for cancer therapy. However, the antitumor effect of glutamine blockade in bladder cancer remains unclear, necessitating further investigation. Here, we demonstrated that glutamine metabolism was involved in the malignant progression of bladder cancer. Treatment with the glutamine antagonist 6-Diazo-5-oxo-L-norleucine (DON) inhibited bladder cancer cells in vitro in several ways. In addition, we observed a remarkable inhibition of tumor growth in bladder cancer-bearing mice using JHU083, a prodrug that was designed to prevent DON-induced toxicity. However, the antitumor immune effect of T cells changed from activation to inhibition as the administrated time extended. We found that both in vitro treatment with DON and in vivo prolonged administration of JHU083 led to the upregulation of PD-L1 in bladder cancer cells. Mechanistically, glutamine blockade up-regulates PD-L1 expression in bladder cancer cells by accumulating ROS, subsequently activating the EGFR/ERK/C-Jun signaling pathway. Combinatorial treatment with JHU083 and gefitinib reversed the up-regulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade. This reversal resulted in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings suggested that broad targeting of glutamine metabolism could represent a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.

2024-08-08 | GSE269520 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-17 | GSE230162 | 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 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

| PRJNA490152 | ENA

Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice

Project description:Combined antiretroviral therapy ushered an era of survivable HIV infection in which people living with HIV (PLH) conduct normal life activities and enjoy measurably extended lifespans. However, despite viral control, PLH often experience a variety of cognitive, emotional, and physical phenotypes that diminish their quality of life, including cognitive impairment, depression, and sleep disruption. Recently, accumulating evidence has linked persistent CNS immune activation to the overproduction of glutamate and upregulation of glutaminase (GLS) activity, particularly in microglial cells, driving glutamatergic imbalance with neurological consequences. Our lab has developed a brain-penetrant prodrug of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), JHU083, that potently inhibits brain GLS activity in mice following oral administration. To assess the therapeutic potential of JHU083, we infected mice with EcoHIV and characterized their neurobehavioral phenotypes. EcoHIV-infected mice exhibited decreased social interaction, suppressed sucrose preference, disrupted sleep during the early rest period, and increased sleep fragmentation, similar to what has been reported in PLH but not yet observed in murine models. At doses shown to inhibit microglial GLS, JHU083 treatment ameliorated all of the abnormal neurobehavioral phenotypes. To explore potential mechanisms underlying this effect, hippocampal microglia were isolated for RNA sequencing. The dysregulated genes and pathways in EcoHIV-infected hippocampal microglia pointed to disruptions in immune functions of these cells, which were partially restored by JHU083 treatment. These findings suggest that upregulation of microglial GLS may affect immune functions of these cells. Thus, brain-penetrable GLS inhibitors like JHU083 could act as a potential therapeutic modality for both glutamate excitotoxicity and aberrant immune activation in microglia in chronic HIV infection.

| S-EPMC9207540 | biostudies-literature

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