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Inosine Induces Stemness Features in HA-CAR-T cells and Enhances Potency [RNA-seq]

ABSTRACT: Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ HA-CAR-T cells commonly express CD39 and CD73, which mediate proximal steps in Ado generation. Here we sought to enhance HA-CAR-T cell potency by knocking out CD39, CD73 or adenosine receptor 2a (A2aR), but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced HA-CAR-T functionality. Similarly, and to a greater extent, exposure of HA-CAR-T cells to INO augmented HA-CAR-T cell function and induced hallmark features of T cell stemness. INO induced profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency HA-CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250442 | GEO | 2023/12/18

REPOSITORIES: GEO

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Inosine Induces Stemness Features in HA-CAR-T cells and Enhances Potency [ATAC-seq]

Project description:Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ HA-CAR-T cells commonly express CD39 and CD73, which mediate proximal steps in Ado generation. Here we sought to enhance HA-CAR-T cell potency by knocking out CD39, CD73 or adenosine receptor 2a (A2aR), but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced HA-CAR-T functionality. Similarly, and to a greater extent, exposure of HA-CAR-T cells to INO augmented HA-CAR-T cell function and induced hallmark features of T cell stemness. INO induced profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency HA-CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.

2023-12-18 | GSE250439 | GEO

Surface AMP Deaminase 2 as a Novel Regulator Modifying Extracellular Adenine Nucleotide Metabolism

Project description:Adenine nucleotides represent crucial immunomodulators in the extracellular environment. The ectonucleotidases CD39 and CD73 are responsible for the sequential catabolism of ATP to adenosine via AMP, thereby promoting an anti-inflammatory milieu induced by the “adenosine halo”. AMPD2 intracellularly mediates AMP deamination to IMP, thus constituting an ambiguous mediator both enhancing the degradation of inflammatory ATP and reducing the formation of protective adenosine. Here, we show that this enzyme is expressed on the cell surface of human immune cells and its predominance may[BF1] modify inflammatory states by altering the extracellular milieu. Surface AMPD2 (eAMPD2) expression on monocytes was verified by immunoblot, mass spectrometry, surface biotinylation, and immunofluorescence microscopy. Flow cytometry revealed enhanced monocytic eAMPD2 expression after TLR stimulation. PBMCs from patients with rheumatoid arthritis displayed significantly higher levels of eAMPD2 expression compared to healthy controls. Furthermore, we observed that extracellular adenosine production was not impaired by an enhanced eAMPD2 expression, while IMP exerted anti-inflammatory effects. In summary, our study identifies eAMPD2 as a novel regulator of the extracellular ATP-adenosine balance adding to the immunomodulatory CD39-CD73 system.

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Co-inhibition of CD73 and a2bar improves long-term cigarette smoke exposure impaired airway wound repair

Project description:Adenosine (ADO) involvement in lung injury depends on the activation of its receptors (A1, A2A, A2B, A3). The A2A receptor (A2AAR) and A2B receptor (A2BAR) are best described to have both tissue-protective and tissue-destructive processes. However, no approach has been effective in delineating the mechanism(s) involved with ADO shifting from its tissue-protective to tissue-destructive properties in chronic airway injury. Using cigarette smoke (CS) as our model of injury, we hypothesized that chronic CS exposure increases CD73-generated ADO which, activates low affinity A2BAR, subsequently impairing airway wound repair. To test this hypothesis, we chronically exposed human bronchial epithelial cell line, Nuli-1 cells, to 5% CS extract (CSE) for three years establishing a long-term CSE exposure model (LTC). We found significant morphological changes, decreased proliferation, and migration resulting in impaired airway wound closure in LTC. Further investigations showed that CSE exposure upregulates CD73 and A2BAR expression, increases ADO production, inhibits PKC alpha activity and phosphorylation of MEK, ERK, p90RSK and CREB. Moreover, when both or either of A2BAR and CD73 are knocked down in LTC, PKC alpha is activated and there is an increase in phosphorylation of MEK, ERK, p90RSK and CREB. Collectively, long-term CSE exposure upregulates CD73 expression and increases ADO production, which promotes A2BAR activation and subsequent diminution of PKC alpha activity and ERK signaling pathway, and inhibition of airway wound repair. Moreover, the data suggested that targeting both A2BAR and CD73 as potential therapeutic targets may be more efficacious in improving chronic CS impaired wound repair than either alone.

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Single Cell Spatial Analysis Reveals the Topology of Immunomodulatory Purinergic Signaling in Glioblastoma

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Comparison of transcription profile of Adenosine receptor (AdoR) null mutant and adenosine transporter (ENT2) partial mutant in Drosophila melanogaster 3rd instar larvae

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2020-10-17 | E-MTAB-8699 | biostudies-arrayexpress

Transcriptional profiling of Adenosine receptor (AdoR) null mutant in Drosophila melanogaster imagoes

Project description:Dysregulation of adenosine (Ado) homeostasis has been observed in both rodent models and human patients of Huntington’s disease (HD). However, the underlying mechanisms of Ado signaling in HD pathogenesis is still unclear. In this study we examined influence of Ado signaling on Drosophila HD model. We further examined the transcription profile of AdoR mutants by microarray analysis to identified a downstream target of AdoR signaling, which mediates the AdoR effects on HD pathology. Our findings have important implications for the crosstalk between Ado signaling and pathogenic effects of HD as well as other human diseases associated with polyglutamine aggregation.

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The Hypoxia-regulated Ectonucleotidase CD73 is a Host Determinant of HIV Latency [RNA-seq]

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