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Enhancing tumor response to adoptive T cell therapy by targeting PHD2/3 in CD8 T cells

ABSTRACT: In our study, we utilized cutting-edge CrisPR-Cas9 technology to evaluate the effects of deleting prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3, which stabilizes HIF-1 signaling, in CD8 T cells that have already undergone differentiation and activation, mirroring the conditions encountered in clinical settings. Our study revealed a significant boost in T-cell activation and effector functions after PHD2/3 deletion, and conclusively established its dependence on HIF-1. This improvement in CD8 T cell performance translated into a remarkable enhancement in the response to adoptive T cell therapy, across various tumor models, even including those reported to be extremely resistant to immunotherapeutic interventions. Furthermore, our data provide compelling evidence that the increased effector functions observed in PHD-deficient (KO) CD8 T cells are intricately linked to an increased glycolytic flux. These findings hold significant promise for advancing CD8 T -cell based therapies and overcoming the immune suppression barriers within challenging tumor microenvironments.

ORGANISM(S): Mus musculus

PROVIDER: GSE271367 | GEO | 2024/07/09

REPOSITORIES: GEO

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PHD2 constrains the anti-tumor CD8+ T cell activity

Project description:The PHD/HIF pathway has been implicated in a wide range of immune and inflammatory processes, including in the oxygen‐deprived tumor microenvironment. To examine the effect of HIF stabilization in anti‐tumor immunity, we deleted Phd2 selectively in T lymphocytes using the cre/lox system. We show that the deletion of PHD2 in lymphocytes resulted in enhanced regression of EG7‐OVA tumors, in a HIF‐1adependent manner. The enhanced control of neoplastic growth correlated with increased poly‐functionality of CD8+ tumor‐infiltrating lymphocytes, i.e. enhanced expression of IFN‐g, TNF‐a and granzyme B. Phenotypic and transcriptomic analyses point to a key role of glycolysis in sustaining CTL activity in the tumor bed and identifies the PHD2/HIF‐1 pathway as potential target for intervention.

2022-12-01 | GSE216536 | GEO

Prolyl hydroxylase domain enzyme PHD2 inhibits proliferation and metabolism in non–small cell lung cancer cells in HIF-dependent and HIF-independent manner

Project description:Prolyl hydroxylase domain protein 2 (PHD2) is one of the intracellular oxygen sensors that mediates proteasomal degradation of hypoxia-inducible factor (HIF)-α via hydroxylation under normoxia. Because of its canonical function in the hypoxia signaling pathway, PHD2 is generally regarded as a tumor suppressor. However, the effects of PHD2 in tumorigenesis are not entirely dependent on HIF-α. Based on the data obtained from The Cancer Genome Atlas (TCGA) database, we found that the expression of PHD2 is upregulated in non-small cell lung cancer (NSCLC), which accounts for approximately 80-85% of lung cancers, suggesting that PHD2 may play an important role in NSCLC. However, the function of PHD2 in NSCLC remains largely unknown. In this study, we established PHD2-deficient H1299 cells to investigate the function of PHD2 in NSCLC, and found that PHD2 suppressed cell proliferation and metabolism, but induced ROS levels in human NSCLC cells. Further results indicated that the function of PHD2 in NSCLC is dependent on its enzymatic activity and partially independent of HIF. Moreover, we performed RNA-seq and transcriptomics analysis to explore the underlying mechanisms, and identified some potential targets and pathways regulated by PHD2, apart from the canonical HIF-mediated hypoxia signaling pathway. These results provide some clues to uncover novel roles of PHD2 in lung cancer progression.

2024-07-17 | GSE239389 | GEO

PHD2/3-dependent hydroxylation of thyroid hormone receptor-Î± mediates the transcriptional regulation of phospholamban to tune the cardiac response to chronic Î²-adrenergic stress

Project description:Ischemic heart disease is the leading cause of heart failure. Both clinical trials and experimental animal studies demonstrate that chronic hypoxia can induce contractile dysfunction even before substantial ventricular damage, implicating a direct role of oxygen in the regulation of cardiac contractile function. Prolyl hydroxylase domain (PHD) proteins are well recognized as oxygen sensors and mediate a wide variety of cellular events by hydroxylating a growing list of protein substrates. Both PHD2 and 3 are highly expressed in the heart, yet their functional roles in modulating contractile function remain incompletely understood. Here, we report that combined deletion of PHD2 and 3 dramatically decreases the expression of phospholamban (PLN), results in sustained activation of CaMKII and sensitizes mice to myocardial injury induced by chronic Î²-adrenergic stress. We provide evidence that thyroid hormone receptor-Î± (TR-Î±), a transcriptional regulator of PLN, interacts with PHD2 and 3 and is hydroxylated at two proline residues. Inhibition of PHDs increases the interaction between TR-Î± and nuclear receptor co-repressor 2 (NCOR2) and suppresses PLN transcription. These observations provide new mechanistic insights into how oxygen directly modulates cardiac contractility, providing the possibility that cardiac function can be modulated therapeutically by tuning PHD enzymatic activity. Two-condition experiment comparing gene expression in hearts isolated from PHD2/3f/f; Cre-/- and PHD2/3f/f; Cre+/- mice. Three biological replicates (mouse hearts) per condition.

2016-04-01 | E-GEOD-67726 | biostudies-arrayexpress

Pseudohypoxia Due to PHD2 Deficiency Induces Endothelial Resistance to Apoptosis and Inflammation Independent of HIF2 alpha via AKT Activation and AIP1 Loss

Project description:PHD2 silencing activated AKT and ERK, inhibited JNK, and decreased AIP1, inhibiting apoptosis and proliferation and activating STAT. Like PHD2, AIP1 silencing affected the same kinase pathways and produced a similar dysfunctional endothelial cell phenotype, which was at least partially reversible with AKT inhibition. Transcriptomic profiling of human lung microvascular endothelial cells revealed that silencing PHD2 or AIP1 both induced an IFN/STAT-biased inflammatory signature with repression of E2F and MYC target genes. These in vitro results mirrored findings in lung vascular endothelial cells and tissues from PAH patients as well as rodent models of PAH. PHD2 deficiency in human lung vascular endothelial cells induced an apoptosis-resistant, inflammatory, and hypo-proliferative phenotype. AKT activation and AIP1 loss, but not HIF signaling, drove these phenotypic aberrations.

2024-11-06 | GSE250030 | GEO

Hypoxia inducible factor prolyl hydroxylase inhibition compromises development and progression of acute myeloid leukaemia

Project description:Acute myeloid leukaemia (AML) is a largely incurable haematological disease, for which new efficient therapeutic strategies are urgently needed. While leukaemogenesis occurs under hypoxic conditions of the bone marrow, the therapeutic tractability of the hypoxia inducible factor (HIF) system in AML is elusive. Given that inactivation of HIF-1α and HIF-2α promotes leukaemic transformation, a possible therapeutic strategy for AML treatment is to constitutively stabilise HIF- α proteins. This can be achieved by targeting the HIF-prolyl hydroxylases (PHDs), the catalysis of which promotes HIF-1α and HIF-2α degradation. Here, we demonstrate that genetic inactivation of Phd1 or Phd2 compromises initiation and progression of AML, without impacting normal haematopoiesis, thus implying the immense therapeutic potential of targeting PHDs in AML. To pharmacologically inactivate PHDs, we employed clinical grade PHD inhibitors as well as a new selective PHD inhibitor (IOX5), which stabilises HIF-α through a novel mechanism of action. Pharmacological PHD inhibition compromises AML cells in a HIF-α dependent manner to disable pro-leukaemogenic pathways in AML cells, re-program their metabolism, and induce cell death, at least in part via pro-apoptotic BNIP3. Importantly, concurrent inhibition of anti-apoptotic BCL-2 by clinically used Venetoclax potentiates the anti-leukaemic effect of PHD inhibition. Thus PHD inhibition with consequent HIF-α stabilisation is a promising new non-toxic strategy for AML treatment.

2024-02-14 | GSE232644 | GEO

Quantitative interactome analysis of PHD2

Project description:To identify novel regulator of EGLN1/PHD2, we performed label-free quantitative interactome analysis. Stable Hela cell lines expressing Flag-tagged PHD2 and control vector were generated. Immunoprecipitation and mass spectrometry analysis were performed to identify novel interactors of PHD2 followed by validation and functional analysis.

2021-09-08 | PXD014757 | Pride

PHD2/3-dependent hydroxylation of thyroid hormone receptor-α mediates the transcriptional regulation of phospholamban to tune the cardiac response to chronic β-adrenergic stress

Project description:Ischemic heart disease is the leading cause of heart failure. Both clinical trials and experimental animal studies demonstrate that chronic hypoxia can induce contractile dysfunction even before substantial ventricular damage, implicating a direct role of oxygen in the regulation of cardiac contractile function. Prolyl hydroxylase domain (PHD) proteins are well recognized as oxygen sensors and mediate a wide variety of cellular events by hydroxylating a growing list of protein substrates. Both PHD2 and 3 are highly expressed in the heart, yet their functional roles in modulating contractile function remain incompletely understood. Here, we report that combined deletion of PHD2 and 3 dramatically decreases the expression of phospholamban (PLN), results in sustained activation of CaMKII and sensitizes mice to myocardial injury induced by chronic β-adrenergic stress. We provide evidence that thyroid hormone receptor-α (TR-α), a transcriptional regulator of PLN, interacts with PHD2 and 3 and is hydroxylated at two proline residues. Inhibition of PHDs increases the interaction between TR-α and nuclear receptor co-repressor 2 (NCOR2) and suppresses PLN transcription. These observations provide new mechanistic insights into how oxygen directly modulates cardiac contractility, providing the possibility that cardiac function can be modulated therapeutically by tuning PHD enzymatic activity.

2016-04-01 | GSE67726 | GEO

mesendoderm differentiation of WT and PHD2 knockout mESCs (scRNA-seq)

Project description:To study the cell composition and gene expression profile in the mesendoderm differentiation of WT and PHD2 knockout, we performed scRNA-seq on the cells collected from the differentiation of WT and PHD2 knockout AB2.2 mESCs at differentiation day 4. PHD2 knockoutout mESCs were constructed by CRISPR/Cas9. The differentiation was performed using a non-lineage tendency differentiation protocol.

2024-09-05 | GSE245439 | GEO

PHD2 constrains the anti-tumor CD8+ T cell activity

Project description:PHD2 constrains the anti-tumor CD8+ T cell activity

| PRJNA894180 | ENA

Adaptaquin is an inhibitor of oxygen-sensing prolyl-hydroxylase domain enzymes that abrogates ATF4-dependent death and improves outcomes from brain hemorrhage

Project description:Disability or death secondary to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron and generation of oxidative stress. Iron chelators bind free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms remain unclear. Here we show that the hypoxia-inducible factor prolylhydroxylase (HIF PHD) family of iron-dependent oxygen sensors is an effector of iron chelation in abrogating ICH-induced death. Molecular reduction of the three HIF PHD isoforms in mouse striatum improves functional recovery following ICH. A low molecular weight, hydroxyquinoline inhibitor of the HIF PHDs, which we call adaptaquin, reduces neuronal death and behavioral deficits following ICH in distinct rodent models. Unexpectedly, adaptaquin protects from oxidative death by suppressing ATF4- dependent prodeath gene expression rather than by activating a HIF-dependent prosurvival pathway. Adaptaquin treated neurons

2016-03-01 | E-GEOD-75048 | biostudies-arrayexpress

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