Tumor Necrosis Factor Alpha-Induced Hypoxia-Inducible Factor 1α–β-Catenin Axis Regulates Major Histocompatibility Complex Class I Gene Activation through Chromatin Remodeling

Ghosh, Sadashib; Paul, Arkoprovo; Sen, Ellora

doi:10.1128/mcb.01254-12

Cited by 45 publications

(24 citation statements)

References 68 publications

(66 reference statements)

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“…As deactivation of IFNGR1 did not lead to the downregulation of the PD-L1 and MHC-I molecules on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vivo compared to TC-1 and TC-1/A9 cells, respectively, we hypothesized that besides IFN-γ, other cytokines induced PD-L1 and MHC-I expression. Several studies have indicated the involvement of different factors (IFN-α, IFN-β, IL-27, EGF, TNF-α, IL-6, GM-CSF, IL-1α, and CCL2 combined with lipocalin 2) in PD-L1 and MHC-I stimulation or stabilization [27,[29][30][31][32][33][34][35][36][37][38][39]. In this study, type I IFNs (IFN-α and IFN-β) were the main inducers of PD-L1 and MHC-I expression.…”

Section: Discussionmentioning

confidence: 99%

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Vackova

Piatakova

Poláková

et al. 2020

IJMS

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Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interferon (IFN)-γ receptor 1 (IFNGR1) in tumor cells can interfere with anti-PD-L1 therapy. For this purpose, we used the mouse oncogenic TC-1 cell line expressing PD-L1 and major histocompatibility complex class I (MHC-I) molecules and its TC-1/A9 clone with reversibly downregulated PD-L1 and MHC-I expression. Using the CRISPR/Cas9 system, we generated cells with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1). In tumors, IFNGR1 deactivation did not lead to PD-L1 or MHC-I reduction on tumor cells. From potential inducers, mainly IFN-α and IFN-β enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-α/IFN-β receptor confirmed the effect of these cytokines in vivo. Combined immunotherapy with PD-L1 blockade and DNA vaccination showed that IFNGR1 deactivation did not reduce tumor sensitivity to anti-PD-L1. Thus, the impairment of IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade, and thus should not be used as a single predictive marker for anti-PD-1/PD-L1 cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Vackova

Piatakova

Poláková

et al. 2020

IJMS

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“…Other signalling mediators that are elevated by tissue inflammation, which include immunometabolites (for example, S-2-hydroxyglutarate), gasotransmitters (for example, nitric oxide (NO) and H 2 S) and reactive oxygen species (ROS) (for example, hydrogen peroxide) also regulate HIF activity in immune cells, thereby contributing to the regulation of immunity and inflammation. Crosstalk also exists between HIF and cyclic AMP-responsive element-binding protein (CREB) in the regulation of MHC class I activation 145 . HIF also regulates the balance between T helper 17 cells and regulatory T cells by binding to the transcription factor forkhead box P3 (FOXP3) 146 and the FOXP3 promoter 147 .…”

Section: Hif Modulation Of Immune Cell Functionmentioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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“…As IDH1 mutation alters the transcriptional program and gene expression in gliomas (5), we examined whether IDH1 mutations affect the status of CD47 in gliomas that exhibit marked difference in effector immune cell functions compared to those of IDH1-WT gliomas (6). Also, since PKM2 regulates ␤-catenin transactivation to affect gliomagenesis (14) and as ␤-catenin regulates major histocompatibility complex class (MHC-I) genes associated with immune-evasive responses in gliomas (22), the possible involvement of PKM2 and ␤-catenin in regulating CD47 associated with immune-evasive responses in IDH1-MT cells was investigated.…”

mentioning

confidence: 99%

Mutant Isocitrate Dehydrogenase 1 Disrupts PKM2–β-Catenin–BRG1 Transcriptional Network-Driven CD47 Expression

Gowda

Patrick

Singh

et al. 2018

Molecular and Cellular Biology

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A gain-of-function mutation in isocitrate dehydrogenase 1 (IDH1) affects immune surveillance in gliomas. As elevated CD47 levels are associated with immune evasion in cancers, its status in gliomas harboring mutant IDH1 (IDH1-MT cells) was investigated. Decreased CD47 expression in IDH1-R132H-overexpressing cells was accompanied by diminished nuclear β-catenin, pyruvate kinase isoform M2 (PKM2), and TCF4 levels compared to those in cells harboring wild-type IDH1 (IDH1-WT cells). The inhibition of β-catenin in IDH1-WT cells abrogated CD47 expression, β-catenin-TCF4 interaction, and the transactivational activity of β-catenin/TCF4. The reverse effect was observed in IDH1-MT cells upon the pharmacological elevation of nuclear β-catenin levels. Genetic and pharmacological manipulation of nuclear PKM2 levels in IDH1-WT and IDH1-MT cells suggested that PKM2 is a positive regulator of the β-catenin-TCF4 interaction. The Cancer Genome Atlas (TCGA) data sets indicated diminished CD47, PKM2, and β-catenin levels in IDH1-MT gliomas compared to IDH1-WT gliomas. Also, elevated BRG1 levels with mutations in the ATP-dependent chromatin-remodeling site were observed in IDH1-MT glioma. The ectopic expression of ATPase-deficient BRG1 diminished CD47 expression as well as TCF4 occupancy on its promoter. Sequential chromatin immunoprecipitation (ChIP-re-ChIP) revealed the recruitment of the PKM2-β-catenin-BRG1-TCF4 complex to the TCF4 site on the CD47 promoter. This occupancy translated into CD47 transcription, as a diminished recruitment of this complex was observed in glioma cells bearing IDH1-R132H. In addition to its involvement in CD47 transcriptional regulation, PKM2-β-catenin-BRG1 cross talk affected the phagocytosis of IDH1-MT cells by microglia.

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Tumor Necrosis Factor Alpha-Induced Hypoxia-Inducible Factor 1α–β-Catenin Axis Regulates Major Histocompatibility Complex Class I Gene Activation through Chromatin Remodeling

Cited by 45 publications

References 68 publications

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Regulation of immunity and inflammation by hypoxia in immunological niches

Mutant Isocitrate Dehydrogenase 1 Disrupts PKM2–β-Catenin–BRG1 Transcriptional Network-Driven CD47 Expression

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