Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma [scRNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE314743 | GEO | 2026/05/19
REPOSITORIES: GEO
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Project description:Despite promising development as emerging “off-the-shelf” therapeutics against cancer, natural killer (NK) cells still faced considerable challenges in the solid tumor microenvironment (TME) including poor penetrance and immuno-suppression. Here, we employed spatial and single-cell transcriptomics to reveal a role for Nur77 in NK cell-mediated immunity against hepatocellular carcinoma (HCC). The expression of NR4A1, encoding Nur77, is associated with NK cell proliferation, activation of the immunostimulatory AP-1 gene regulons and better disease-free survival in HCC. Conditional ablation of Nr4a1 in NK cells perturbed their homeostasis and accelerated tumor progression in multiple tumor models while the agonistic activation of Nur77 in NK cells ex-vivo or in-vivo enhanced their anti-tumor functions. Mechanistically, Nur77 activation attenuated CD36 expression in NK cells and conferred resistance against oxLDL-mediated immunosuppression in the TME. Collectively, our findings highlighted the potential of harnessing Nur77 agonism in improving NK cell-based immunotherapy against tumors.
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Project description:Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphphotase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis, and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an EZH2-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived EVs, dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.
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Project description:Pancreatic ductal adenocarcinoma ranks among the most aggressive malignancies and exhibits a higher prevalence and poorer prognosis in male patients. Natural killer cells play a critical role in tumor immunosurveillance by directly recognizing and eliminating tumor cells. It is well established that females generally mount stronger immune responses than males. The present study aims to answer the question of whether sex has an influence on the NK cell-mediated anti-tumor function in PDAC. To validate our in vitro findings in a physiological context, we employed a syngeneic allograft mouse model.
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Project description:<p>Natural killer (NK) cells are forced to cope with different oxygen environments even under resting conditions. The adaptation to low oxygen is regulated by oxygen-sensitive transcription factors, the hypoxia-inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining <em>in situ</em> metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF-1a as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD+) levels. The HIF-1a/NAD+ axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steadystate conditions. In contrast, in activated NK cells under hypoxia, HIF-1a is required for glycolysis, and forced HIF-1a expression boosts glycolysis and NK cell performance <em>in vitro</em> and <em>in vivo</em>. Our data highlight two distinct pathways by which HIF-1a interferes with NK cell metabolism. While HIF-1a-driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF-1a-dependent tryptophan/NAD+ metabolism.</p><p><br></p><p><strong>Linked cross omic data sets:</strong></p><p>RNA-seq data associated with this study are available in ArrayExpress (BioStudies): accession <a href='https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-12082' rel='noopener noreferrer' target='_blank'>E-MTAB-12082</a>.</p>
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Project description:The maturation process determines NK cell functionality. We verified that tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2) works as a potent negative regulator in NK cell maturation. We found that TIPE2 expression gradually increased during NK cell ontogenesis correlating to their maturation stages in mice. NK-specific TIPE2 deficiency resulted in increased number of mature NK cells. To further confirm the role of TIPE2 in NK cell maturation, we performed single-cell RNA sequencing. Based on the key gene expression of NK cell effector molecules, transcriptional factors, maturation markers, and proliferation marker, we identified NK cell maturation program as Cluster#1->Cluster#2->Cluster#0 by which immature NK cells should go through to gain optimal effector functions at the cost of proliferation ability. According to this model, NK-specific TIPE2 deficient mice contained more NK cells belonging to the terminally mature Cluster#0 than control mice (up to 10% more), which is consistent with what we observed by flow cytometry. Therefore, these results collectively showed that NK-specific TIPE2 deficiency promotes NK cell maturation.
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Project description:In this study we aim to explore the metabolic enzyme that affects NK cell function in colorectal cancer, and mainly focus on the mechanism how nuclear ACAT1（Mitochondrial acetyl-CoA acetyltransferase）promotes NK cell infiltration and activation
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Project description:Human NK cells were treated with IL-12/15/18 to induce trained immunity. scRNA-seq and TotalSeqTM were performed to map the development pathway of trained NK cells.
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Project description:Purified NK cells were co-cultured with M. bovis BCG or M. tuberculosis H37Rv (1:1) in the presence of IL-2 (100U/ml) or IL-12 (10pg/ml) for 24h before trizol extraction. We used microarrays to detail the global gene expression underlying NK cell activation by mycobacteria. NK cell were isolated from the blood of 6 independent donors and activated with different mycobacteria and cytokines in order to study their transcriptional profiles according to mycobacterial virulence.
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2016-10-07 | PXD002206 | Pride