Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1099132 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Natural killer (NK) cell development and functionality rely on precise regulation by specific transcription factors (TFs). Our study demonstrates that the nuclear orphan receptor NR2F6 represses the expression of the activating receptor NKp46, an established key player in NK cell-mediated cytotoxicity during infection and tumor rejection. Despite normal NK cell development in the bone marrow, germline Nr2f6-deficient mice exhibit impaired terminal maturation of NK cells in the periphery. Short-term NK cell responses to lipopolysaccharide (LPS) activation, independent of NKp46, are subsequently reduced in Nr2f6-deficient mice. Conventional type 1 dendritic cells (cDC1) and macrophage populations are decreased in spleens of Nr2f6-deficient mice, subsequently, IL-15-dependent NK cell priming is limited. Administration of exogenous IL-15 in vitro and as IL-15 complex in vivo can compensate for these deficits, promoting terminal maturation of NK cells in Nr2f6-deficient mice. Subsequent transcriptome analysis reveals significant changes in gene expression profiles of NK cells from IL-15 complex treated Nr2f6-deficient mice, with notable alterations in essential NK genes such as Klrg1, Prdm1, Stat5a, Zeb2, and Prf1. Consequently, Nr2f6-deficient IL-15 complex treated NK cells raise enhanced effector responses of IFNγ, Perforin, and Granzyme B upon ex vivo activation. Of importance, Nr2f6-deficient mice are protected against MHC-I negative B16-F10 melanoma lung metastasis formation, especially with IL-15 complex treatment, indicating the potential of NR2F6 to affect NKp46-dependent NK cell-mediated tumor surveillance. The therapeutic targeting of NR2F6 may be a promising strategy for boosting NKp46-dependent NK-cell-mediated tumor surveillance and metastasis.
2025-02-10 | GSE263734 | GEO
Project description:Nuclear receptors (NRs) are implicated in the regulation of tumors and immune cells. We identify a tumor-intrinsic function of the orphan NR, NR2F6, regulating anti-tumor immunity. NR2F6 was selected from 48 candidate NRs, based on an expression pattern in melanoma patient specimens (i.e., IFN signature) associated with positive responses to immunotherapy and favorable patient outcomes. Correspondingly, genetic ablation of NR2F6 in a mouse melanoma model conferred a more effective response to PD-1 therapy. NR2F6 loss in B16F10 and YUMM1.7 melanoma cells attenuated tumor development in immune-competent but not -incompetent mice via the increased abundance of effector and progenitor-exhausted CD8+ T cells. Inhibition of NACC1 and FKBP10, identified as NR2F6 effectors, phenocopied NR2F6 loss. Remarkably, inoculation of NR2F6 KO mice with NR2F6 KD melanoma cells further decreased tumor growth compared with NR2F6 WT mice. Tumor-intrinsic NR2F6 function complements its tumor-extrinsic role and justifies the development of novel anti-cancer therapies.
2023-09-11 | GSE228162 | GEO
Project description:Analyzing mouse tumor models in vivo, human T cells ex vivo and human lung cancer samples, we provide direct evidence that NR2F6 acts as novel immune checkpoint. Genetic ablation of Nr2f6, particularly in combination with blockade of the established PD-L1 cancer immune checkpoint, efficiently delayed tumor progression and improved survival in experimental mouse models. The target genes deregulated in intratumoral T lymphocytes upon genetic ablation of Nr2f6 alone or together with PD-L1 blockade, revealed multiple advantageous transcriptional alterations for effective tumor rejection. In keeping with the above observation, acute Nr2f6 silencing in both mouse and human T cells induced hyper-responsiveness that established a non-redundant T cell-inhibitory function of NR2F6. Analyzing mouse tumor models in vivo, human T cells ex vivo and human lung cancer samples,
2018-03-14 | GSE111796 | GEO
Project description:In mouse models, the bromodomain PHD finger transcription factor (BPTF) chromatin remodeling subunit in tumor cells suppresses natural killer (NK) cell antitumor activity. In vitro, BPTF suppresses NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating a conserved function.
2017-04-28 | GSE85756 | GEO
Project description:The regulation of proper gene transcription is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is widely used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we perform H3K27ac ChIP-Seq analysis to profile the active enhancer pattern in HSV-1-infected THP-1 cells. We have identified three transcription factors, NR2F6, MEF2D and MAFF, and experimentally verified their roles in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, which is not related with the classical cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activate AP-1/c-Jun pathway, which is critical for DNA virus replication. On the contrary, NR2F6 expression is transcriptionally repressed by c-Jun upon HSV-1 infection, which forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors involved in the interactive network between DNA viruses and host cells, and revealed the underlying mechanisms for anti-viral research.
2024-05-30 | GSE249664 | GEO
Project description:The regulation of proper gene transcription is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is widely used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we perform H3K27ac ChIP-Seq analysis to profile the active enhancer pattern in HSV-1-infected THP-1 cells. We have identified three transcription factors, NR2F6, MEF2D and MAFF, and experimentally verified their roles in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, which is not related with the classical cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activate AP-1/c-Jun pathway, which is critical for DNA virus replication. On the contrary, NR2F6 expression is transcriptionally repressed by c-Jun upon HSV-1 infection, which forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors involved in the interactive network between DNA viruses and host cells, and revealed the underlying mechanisms for anti-viral research.
2024-05-30 | GSE249663 | GEO
Project description:NK cells engineered to express IL-21 (IL-21 NK) acquire strong antitumor activity, with the ability to respond to glioblastoma (GBM) rechallenge in vitro and in vivo. IL-21 NK cells have a unique signature of chromatin accessibility, with CCAAT/Enhancer-Binding Protein (C/EBP), especially CEBPD, serving as key transcription factors regulating their memory response.
2024-07-09 | GSE227098 | GEO
Project description:The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity
| PRJNA1050145 | ENA
Project description:Natural killer (NK) cells are the main innate antitumor effector cells and can be constrained in the tumor microenvironment (TME). It has been reported that E3 ligase FBXO38 accelerates PD-1 degradation of tumor-infiltrating T cells to unleash their cytotoxic function. In this study, we found that FBXO38 transcripts were significantly lower in intra-tumoral NK cells than in peri-tumoral regions using specimens from cancer patients in The Cancer Genome Atlas (TCGA). Conditional knock-out (cKO) of FBXO38 in NK cells accelerated tumor growth and increased tumor metastasis. However, FBXO38 deficiency did not show an effect on the cytotoxic function of tumor-infiltrating NK (TINK) cells, but decreased proliferation and survival of TINK cells. Mechanically, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL-15 by reducing the expression of IL-15Rβ and IL-15Rγc, which accounted for the reduced expansion of FBXO38-deficient TINK cells in TME. Furthermore, human NK-92 cells proliferated more rapidly when FBXO38 was overexpressed and exerted greater antitumor efficacy in xenograft mouse models. Conversely, the removal of FBXO38 led to a dramatic decrease in NK-92 cell proliferation. In conclusion, our results suggest that FBXO38 strongly sustains NK cell expansion in the antitumor immunity response.
2024-01-31 | GSE253993 | GEO
Project description:Our previous work indicated that the Enhancer of Zeste Homolog 2 (Ezh2) is a negative regulator of NK cell early differentiation and function by trimethylation of histone H3 lysine 27 (H3K27me3). Here, we deleted Ezh2 from immature NK and downstream progeny to explore its role in NK cell maturation by single-cell RNA sequencing (scRNA-seq). We identified six distinct NK stages based on transcriptional signature during the maturation of NK cells. Conditional deletion of Ezh2 in NK cells resulted in the maturation trajectory of NK cell arrested in CD11b SP stage 5 which is clustered with genes related to activating function of NK cells. Mechanistically, we speculated that Ezh2 plays a critical role in NK development by activating gene expression of the AP-1 superfamily independent of PRC2 function. Our results implied a novel role for the Ezh2-AP-1-Klrg1 axis to alter NK cell maturation trajectory and NK cell-mediated cytotoxicity.
2021-07-07 | GSE179186 | GEO