Amino Acid Transport and Metabolism in Myeloid Function

Halaby, Marie Jo; McGaha, Tracy L.

doi:10.3389/fimmu.2021.695238

Cited by 23 publications

(19 citation statements)

References 73 publications

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“…[ 35 ] Glutamine metabolism has also been reported to be critical for the recruitment and functional activity of MDSCs. [ 36 ] Glutamine antagonism has successfully resulted in reduced MDSC infiltration into the TME. [ 10 , 36 ] We found that JHU083 inhibited M‐MDSCs in our tumor model.…”

Section: Discussionmentioning

confidence: 99%

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Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

et al. 2022

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Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR‐driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single‐cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8+ T cell and CD4+ Th1 cell infiltration, while EVax elicits robust Th1 cell‐mediated immune responses and protects mice against EGFRL858R mutation‐driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic‐ and granulocytic‐myeloid‐derived suppressor cells, regulatory T cells, and pro‐tumor CD4+ Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory‐like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR‐driven lung tumorigenesis and promotes an adaptive T cell‐mediated tumor‐specific immune response that enhances the efficacy of EVax.

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Section: Discussionmentioning

confidence: 99%

“…[ 36 ] Glutamine antagonism has successfully resulted in reduced MDSC infiltration into the TME. [ 10 , 36 ] We found that JHU083 inhibited M‐MDSCs in our tumor model. The inhibition of glutamine metabolism and OXPHOS enhanced apoptosis and autophagy pathways, which could be the potential reason for the decrease in M‐MDSCs.…”

Section: Discussionmentioning

confidence: 99%

Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

et al. 2022

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“…The metabolism of arginine serves as a key regulator of innate and adaptive immunity [ 7 , 8 , 9 , 10 , 11 ]. Arginine catabolism in myeloid cells is largely driven by nitric oxide (NO) synthase (NOS) and arginase (ARG), and the differential regulation of these enzymes augments or diminishes the immune response.…”

Section: Introductionmentioning

confidence: 99%

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

Durante

2022

Metabolites

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Coronavirus disease 2019 (COVID-19) represents a major public health crisis that has caused the death of nearly six million people worldwide. Emerging data have identified a deficiency of circulating arginine in patients with COVID-19. Arginine is a semi-essential amino acid that serves as key regulator of immune and vascular cell function. Arginine is metabolized by nitric oxide (NO) synthase to NO which plays a pivotal role in host defense and vascular health, whereas the catabolism of arginine by arginase to ornithine contributes to immune suppression and vascular disease. Notably, arginase activity is upregulated in COVID-19 patients in a disease-dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO. This rewiring of arginine metabolism in COVID-19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti-organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular disease in patients with COVID-19.

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“…Accordingly, we strengthened this finding in another group of experiments with BMDMs separated from GBM samples (Figure 2B) and confirmed it in an in vitro model of immunosuppressive macrophages derived from blood monocytes of HDs (Figure 2B, Mφ), whose relevant suppressive activity and HO‐1 expression (Figure S1) justified their use in investigating HO‐1‐related immunosuppressive mechanisms. Previous studies from us and others identified the contribution of the IDO1 and ARG‐1 enzymes in different immunosuppressive myeloid populations 7,20,21 . For this reason, we evaluated the effect of the IDO1 inhibitor 1‐MT and ARG‐1/ARG‐2 inhibitor Nor‐NOHA (NN).…”

Section: Resultsmentioning

confidence: 99%

The immunosuppression pathway of tumor‐associated macrophages is controlled by heme oxygenase‐1 in glioblastoma patients

Magri

Musca

Pinton

et al. 2022

Intl Journal of Cancer

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The immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is mainly driven by tumor‐associated macrophages (TAMs). We explored whether their sustained iron metabolism and immunosuppressive activity were correlated, and whether blocking the central enzyme of the heme catabolism pathway, heme oxygenase‐1 (HO‐1), could reverse their tolerogenic activity. To this end, we investigated iron metabolism in bone marrow‐derived macrophages (BMDMs) isolated from GBM specimens and in in vitro‐derived macrophages (Mφ) from healthy donor (HD) blood monocytes. We found that HO‐1 inhibition abrogated the immunosuppressive activity of both BMDMs and Mφ, and that immunosuppression requires both cell‐to‐cell contact and soluble factors, as HO‐1 inhibition abolished IL‐10 release, and significantly reduced STAT3 activation as well as PD‐L1 expression. Interestingly, not only did HO‐1 inhibition downregulate IDO1 and ARG‐2 gene expression, but also reduced IDO1 enzymatic activity. Moreover, T cell activation status affected PD‐L1 expression and IDO1 activity, which were upregulated in the presence of activated, but not resting, T cells. Our results highlight the crucial role of HO‐1 in the immunosuppressive activity of macrophages in the GBM TME and demonstrate the feasibility of reprogramming them as an alternative therapeutic strategy for restoring immune surveillance.

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Amino Acid Transport and Metabolism in Myeloid Function

Cited by 23 publications

References 73 publications

Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

The immunosuppression pathway of tumor‐associated macrophages is controlled by heme oxygenase‐1 in glioblastoma patients

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