The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance

Hermann-Kleiter, Natascha; Klepsch, Victoria; Wallner, Stephanie; Siegmund, Kerstin; Klepsch, Sebastian; Tuzlak, Selma; Kaminski, Sandra; Pfeifhofer-Obermair, Christa; Gruber, Thomas; Wolf, Dominik; Baier, Gottfried

doi:10.1016/j.celrep.2015.08.035

Cited by 47 publications

(79 citation statements)

References 43 publications

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“…Based on previous studies and our present research, we believe that NR2F6 may also serve as a valuable druggable target. Recent studies indicate that NR2F6 serves as an immune checkpoint regulator that suppresses adaptive anticancer immune responses; this sets the stage for clinical validation of targeting NR2F6 for next‐generation immune‐oncological treatment regimens . Notably, Hermann‐Kleiter et al .…”

Section: Discussionmentioning

confidence: 99%

“…demonstrated that NR2F6 appears to be an intracellular immune checkpoint in effector T cells, directly repressing the NFAT/AP‐1 complex on both the interleukin 2 and interferon and cytokine promoters, attenuating their transcription. Moreover, adoptive transfer of Nr2f6‐deficient T cells into tumor‐bearing immune competent mice was shown to be sufficient to delay tumor outgrowth . Importantly, a previous study indicated that the ligand binding domain (LBD) on NR2F6 is highly evolutionarily conserved and appears to be essential for NR2F6 transcriptional activity .…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that NR2F6 serves as an immune checkpoint regulator that suppresses adaptive anticancer immune responses; this sets the stage for clinical validation of targeting NR2F6 for next-generation immune-oncological treatment regimens. 10,45 Notably, Hermann-Kleiter et al 45 demonstrated that NR2F6 appears to be an intracellular immune checkpoint in effector T cells, directly repressing the NFAT/AP-1 complex on both the interleukin 2 and interferon and cytokine promoters, attenuating their transcription. Moreover, adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immune competent mice was shown to be sufficient to delay tumor outgrowth.…”

Section: Discussionmentioning

confidence: 99%

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Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway

Zhang

Niu

et al. 2019

Intl Journal of Cancer

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The primary challenge facing treatment of epithelial ovarian cancer (EOC) is the high frequency of chemoresistance, which severely impairs the quality of life and survival of patients with EOC. Our study aims to investigate the mechanisms by which upregulation of NR2F6 induces chemoresistance in EOC. The biological roles of NR2F6 in EOC chemoresistance were explored in vitro by Sphere, MTT and AnnexinV/PI assay, and in vivo using an ovarian cancer orthotopic transplantation model. Bioinformatics analysis, luciferase assay, CHIP and IP assays were performed to identify the mechanisms by which NR2F6 promotes chemoresistance in EOC. The expression of NR2F6 was significantly upregulated in chemoresistant EOC tissue, and NR2F6 expression was correlated with poorer overall survival. Moreover, overexpression of NR2F6 promotes the EOC cancer stem cell phenotype; conversely, knockdown of NR2F6 represses the EOC cancer stem cell phenotype and sensitizes EOC to cisplatin in vitro and in vivo. Our results further demonstrate that NR2F6 sustains activated Notch3 signaling, resulting in chemoresistance in EOC cells. Notably, NR2F6 acts as an informative biomarker to identify the population of EOC patients who are likely to experience a favorable objective response to gamma‐secretase inhibitors (GSI), which inhibit Notch signaling. Therefore, concurrent inhibition of NR2F6 and treatment with GSI and cisplatin‐based chemotherapy may be a novel therapeutic approach for NR2F6‐overexpressing EOC. In summary, we have, for the first time, identified an important role for NR2F6 in EOC cisplatin resistance. Our study suggests that GSI may serve as a potential targeted treatment for patients with NR2F6‐overexpressing EOC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway

Zhang

Niu

et al. 2019

Intl Journal of Cancer

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“…Furthermore, they found that NR2F6 deletion has the same effect as blocking PD-1/PD-L1 interaction, considered an established immune checkpoint mechanism. They also found that NR2F6 directly represses the transcription of cytokine genes in T cells related to cancer cell rejection, such as interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ [39]. Therefore, NR2F6 may be a potential cancer therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer

Niu

Sun

Zhang

et al. 2016

IJMS

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Background: There is an abnormal expression of nuclear receptor subfamily 2 group F member 6 (NR2F6) in human cancers such as breast cancer, colon cancer, and acute myelogenous leukemia. However, its clinical significance in cervical cancer has not been established. We explored NR2F6 expression and its clinicopathological significance in early-stage cervical cancer. Methods: NR2F6 expression in cervical cancer cell lines and cervical cancer tissues was determined by Western blotting, real-time PCR, and immunochemistry (IHC). NR2F6 expression in 189 human early-stage cervical cancer tissue samples was evaluated using IHC. The relevance between NR2F6 expression and early-stage cervical cancer prognosis and clinicopathological features was determined. Results: There was marked NR2F6 mRNA and protein overexpression in the cervical cancer cells and clinical tissues compared with an immortalized squamous cell line and adjacent noncancerous cervical tissues, respectively. In the 189 cervical cancer samples, NR2F6 expression was positively related to International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.006), squamous cell carcinoma antigen (p = 0.006), vital status (p < 0.001), tumor recurrence (p = 0.001), chemotherapy (p = 0.039), and lymph node metastasis (p < 0.001). Overall and disease-free survival was shorter in patients with early-stage cervical cancer and higher NR2F6 levels than in patients with lower levels of NR2F6. Univariate and multivariate analysis determined that NR2F6 was an independent prognostic factor of survival in early-stage cervical cancer. Conclusions: Taken together, our findings suggest that high NR2F6 expression predicts pelvic lymph node metastasis, tumor recurrence and poor prognosis in early-stage cervical cancer. NR2F6 might be a novel prognostic biomarker and potential therapeutic target of cervical cancer.

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“…Reviews on NGFI-B-mediated pathways refer to references [7,[84][85][86]. [49]. It waits to demonstrate whether manipulation of the immune system via EAR2 would be a potential strategy for the immunotherapy of prostate cancer.…”

Section: Coup-tfsmentioning

confidence: 99%

The emerging roles of orphan nuclear receptors in prostate cancer

Cheung

Wang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Orphan nuclear receptors are members of the nuclear receptor (NR) superfamily and are so named because their endogenous physiological ligands are either unknown or may not exist. Because of their important regulatory roles in many key physiological processes, dysregulation of signalings controlled by these receptors is associated with many diseases including cancer. Over years, studies of orphan NRs have become an area of great interest because their specific physiological and pathological roles have not been well-defined, and some of them are promising drug targets for diseases. The recently identified synthetic small molecule ligands, acting as agonists or antagonists, to these orphan NRs not only help to understand better their functional roles but also highlight that the signalings mediated by these ligand-independent NRs in diseases could be therapeutically intervened. This review is a summary of the recent advances in elucidating the emerging functional roles of orphan NRs in cancers, especially prostate cancer. In particular, some orphan NRs, RORγ, TR2, TR4, COUP-IFII, ERRα, DAX1 and SHP, exhibit crosstalk or interference with androgen receptor (AR) signaling in either normal or malignant prostatic cells, highlighting their involvement in prostate cancer progression as androgen and AR signaling pathway play critical roles in this process. We also propose that a better understanding of the mechanism of actions of these orphan NRs in prostate gland or prostate cancer could help to evaluate their potential value as therapeutic targets for prostate cancer.

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The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance

Cited by 47 publications

References 43 publications

Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway

Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway

NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer

The emerging roles of orphan nuclear receptors in prostate cancer

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