The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids

Griffett, Kristine; Bedia-Diaz, Gonzalo; Hegazy, Lamees; Vera, Ian Mitchelle S. de; Wanninayake, Udayanga; Billon, Cyrielle; Koelblen, Thomas; Wilhelm, McKenna; Burris, Thomas P.

doi:10.1016/j.chembiol.2020.07.013

Cited by 18 publications

(38 citation statements)

References 58 publications

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“…21 22 Additionally, TLX plays an oncogenic role in promoting the development of prostate cancer through inhibition of oncogene-induced cellular senescence, 23 and progression of prostate cancer towards castrationresistance via transcriptional repression of the AR gene. 24 Furthermore, both natural and synthetic retinoids, such as BMS453, bind directly to TLX and regulate its transcriptional activity, 25 suggesting that targeting TLX may be of potential therapeutic significance in human cancers. However, the expression of TLX in human gliomas, and its functional role in immune escape, have not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma

Zhou

Pei

Yang

et al. 2021

J Immunother Cancer

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BackgroundHigh-grade gliomas are rapidly progressing tumors of the central nervous system, and are associated with poor prognosis and highly immunosuppressive microenvironments. Meanwhile, a better understanding of PD-L1, a major prognostic biomarker for checkpoint immune therapy, regulation may provide insights for developing novel immunotherapeutic strategies for treating gliomas. In the present study, we elucidate the functional significance of the orphan nuclear receptor TLX in human glioma, and its functional role in immune suppression through regulation of PD-L1/PD-1 axis.MethodsTLX and PD-L1 expression patterns, and their association with clinicopathological parameters and immune phenotypes of glioma were analysed using CIBERSORT algorithm and single-sample gene-set enrichment analysis from The Cancer Genome Atlas (n=695) and Chinese Glioma Genome Atlas (n=1018) databases. Protein expression and cellular localization of TLX, PD-L1, and PD-1, as well as the prevalence of cytotoxic tumor-infiltrating lymphocytes (TILs), and tumor-associated macrophages (TAMs), in the glioma immune microenvironment were analyzed via tissue microarray by immunohistochemistry and multiplex immunofluorescence. Glioma allografts and xenografts with TLX manipulation (knockdown/knockout or reverse agonist) were inoculated subcutaneously, or orthotopically into the brains of immunodeficient and immunocompetent mice to assess tumor growth by imaging, and the immune microenvironment by flow cytometry. PD-L1 transcriptional regulation by TLX was analyzed by chromatin immunoprecipitation and luciferase reporter assays.ResultsTLX and PD-L1 expression was positively associated with macrophage-mediated immunosuppressive phenotypes in gliomas. TLX showed significant upregulation and positive correlation with PD-L1. Meanwhile, suppression of TLX significantly inhibited in vivo growth of glioma allografts and xenografts (p<0.05), rescued the antitumoral immune response, significantly decreased the PD-L1+, and glioma-associated macrophage population, and increased cytotoxic lymphocyte infiltration (p<0.05). Mechanistically, TLX binds directly to CD274 (PD-L1) gene promoter and activates CD274 transcription.ConclusionsTLX contributes to glioma malignancy and immunosuppression through transcriptional activation of PD-L1 ligands that bind to PD-1 expressed on both TILs and TAMs. Thus, targeting the druggable TLX may have potential therapeutic significance in glioma immune therapy.

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Section: Introductionmentioning

confidence: 99%

Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma

Zhou

Pei

Yang

et al. 2021

J Immunother Cancer

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“…In this context, the orphan nuclear receptor tailless (TLX) is one of the mediators downstream of HIF signaling produced by astrocytes that has an important role during retinal development [ 34 ]. TLX (NR2E1), a nuclear receptor that acts as a transcription factor, is predominantly expressed in the central nervous system, and has a critical role in the embryonic and adult neurogenic process and neural development, especially in the visual system [ 35 , 36 , 37 ]. Studies from Uemura et al showed that TLX expression increases in proangiogenic astrocytes and has a crucial role in the formation of the extracellular scaffold formed by these astrocytes through the upregulation of the expression and extracellular deposition of fibronectin, which provides the optimal conditions for survival, adhesion, and migration of ECs [ 34 ].…”

Section: Astrocytes As Templates For Angiogenesismentioning

confidence: 99%

Key Role of Astrocytes in Postnatal Brain and Retinal Angiogenesis

Puebla

Tapía

Espinoza³

2022

IJMS

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Angiogenesis is a key process in various physiological and pathological conditions in the nervous system and in the retina during postnatal life. Although an increasing number of studies have addressed the role of endothelial cells in this event, the astrocytes contribution in angiogenesis has received less attention. This review is focused on the role of astrocytes as a scaffold and in the stabilization of the new blood vessels, through different molecules release, which can modulate the angiogenesis process in the brain and in the retina. Further, differences in the astrocytes phenotype are addressed in glioblastoma, one of the most devastating types of brain cancer, in order to provide potential targets involved in the cross signaling between endothelial cells, astrocytes and glioma cells, that mediate tumor progression and pathological angiogenesis. Given the relevance of astrocytes in angiogenesis in physiological and pathological conditions, future studies are required to better understand the interrelation between endothelial and astrocyte signaling pathways during this process.

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“…TLX is an evolutionary conserved nuclear receptor that plays a critical role in embryonic and adult neurogenesis 65,66 . It is usually found in proliferating neural progenitors, regulating adult neural stem cell renewal 65,66,67 . It has been suggested that retinoids can act as ligands 65 .…”

Section: Tlx Receptormentioning

confidence: 99%

“…It is usually found in proliferating neural progenitors, regulating adult neural stem cell renewal 65,66,67 . It has been suggested that retinoids can act as ligands 65 . Aberrations in the TLX gene leads to loss of neurogenesis, retinopathies, psychiatric conditions and nervous system tumors.…”

Section: Tlx Receptormentioning

confidence: 99%

Orphan Receptors in Prostate Cancer

Sakellakis¹

2022

Preprint

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Background: The identification of new cellular receptors has been increasing rapidly. A receptor is called “orphan” if an endogenous ligand has not been identified yet. Methods: Here we review receptors that contribute to prostate cancer and are considered orphan or partially orphan. This means that the full spectrum of their endogenous ligands remains unknown. Results: The orphan receptors are divided into two major families. The first group includes G protein-coupled receptors. Most are orphan olfactory receptors. OR51E1 inhibits cell proliferation and induces senescence in prostate cancer. OR51E2 inhibits prostate cancer growth, but promotes invasiveness and metastasis. GPR158, GPR110 and GPCR-X play significant roles in prostate cancer development and progression. However, GPR160 induces cell cycle arrest and apoptosis. The other major subset of orphan receptors are nuclear receptors. RORα inhibits tumor growth, but RORγ stimulates androgen receptor signaling. PXR contributes to metabolic deactivation of androgens and inhibits cell proliferation. TLX has pro-tumorigenic effects in prostate cancer, while its knockdown triggers cellular senescence and growth arrest. Estrogen-related receptor ERRγ can inhibit tumor growth but ERRα is pro-tumorigenic. Dax1 and Shp are also inhibitory in prostate cancer. Conclusion: There is a “zoo” of relatively underappreciated orphan receptors that play key roles in prostate cancer.

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The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids

Cited by 18 publications

References 58 publications

Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma

Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma

Key Role of Astrocytes in Postnatal Brain and Retinal Angiogenesis

Orphan Receptors in Prostate Cancer

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