scholarly journals Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2600
Author(s):  
Victoria Klepsch ◽  
Kerstin Siegmund ◽  
Gottfried Baier
Keyword(s):  
T Cells ◽  
Nuclear Receptor ◽  
Immune Checkpoint ◽  
Immune Therapy ◽  
Treatment Options ◽  
Orphan Nuclear Receptor ◽  
Oncology Research ◽  
Gene Ablation ◽  
Surface Receptor ◽  
Promising Perspective

Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside effector CD4+ and CD8+ T cells. It is likely that future treatment options will combine surface receptor and intracellular protein targets. Utilizing germline gene ablation as well as CRISPR/Cas9-mediated acute gene mutagenesis, the nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) has been firmly characterized as such an intracellular immune checkpoint in effector T cells. Targeting this receptor appears to be a strategy for improving anti-tumor immunotherapy responses, especially in combination with CTLA-4 and PD-1. Current preclinical experimental knowledge firmly validates the immune checkpoint function of NR2F6 in murine tumor models, which provides a promising perspective for immunotherapy regimens in humans in the near future. While the clinical focus remains on the B7/CD28 family members, protein candidate targets such as NR2F6 are now being investigated in laboratories around the world and in R&D companies. Such an alternative therapeutic approach, if demonstrated to be successful, could supplement the existing therapeutic models and significantly increase response rates of cancer patients and/or expand the reach of immune therapy regimens to include a wider range of cancer entities. In this perspective review, the role of NR2F6 as an emerging and druggable target in immuno-oncology research will be discussed, with special emphasis on the unique potential of NR2F6 and its critical and non-redundant role in both immune and tumor cells.

scholarly journals Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Victoria Klepsch ◽  
Maria Pommermayr ◽  
Dominik Humer ◽  
Natascha Brigo ◽  
Natascha Hermann-Kleiter ◽  
...  
Keyword(s):  
T Cells ◽  
Nuclear Receptor ◽  
Immune Checkpoint ◽  
Orphan Nuclear Receptor

The Orphan Nuclear Receptor NR2F6 Is a Novel Negative Regulator of T-Cell Development.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 915-915
Author(s):  
Christine V. Ichim ◽  
Dzana Dervovic ◽  
Juan Carlo Zuniga-Pflucker ◽  
Richard A. Wells
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Nuclear Receptor ◽  
Bone Marrow Cells ◽  
Orphan Nuclear Receptor ◽  
Over Expression ◽  
Competitive Disadvantage ◽  
Marrow Cells

Abstract Abstract 915 The orphan nuclear receptor NR2F6 is a mammalian homologue of the Drosophila seven-up gene that plays key roles in decisions of cell fate in neuroblast and retinal cells. We have previously described a novel role for NR2F6 in decisions of cell fate of mammalian haematopoietic cells of the myeloid cell lineage. We have shown that over-expression of NR2F6 in bone marrow cells impairs differentiation and extends the proliferative capacity of myeloid and early progenitor cells eventually leading to acute myeloid leukaemia (AML), while silencing of NR2F6 expression in AML cell lines causes terminal differentiation and apoptosis. A role of NR2F6 in lymphopoiesis has yet to be identified. Here we describe for the first time a role for NR2F6 in the specification of lymphoid cells. NR2F6 expression is heterogeneous throughout the haematopoietic hierarchy, with expression being highest in long-term repopulating HSCs and generally declining with the differentiation of progenitor cells. We report that over-expression of NR2F6 abrogates the developmental program necessary for T-cell lymphopoiesis. We assessed the effects of NR2F6 on lymphopoiesis in vivo by competitive bone marrow transplantation of NR2F6-IRES-GFP or GFP retrovirally transduced grafts (n=43). Competitive repopulation of lethally irradiated murine hosts with GFP transduced bone marrow cells resulted in successful engraftment and T-cell development, with GFP+ T-cells present in the thymus, and periphery at rates comparable to the percent marked cells in the original graft. However over-expression of NR2F6 placed developing T-cells at a dramatic competitive disadvantage. Six weeks post transplant the proportion of CD3+ cells derived from NR2F6 transduced bone marrow cells was greatly diminished relative to control (more than 10 fold), while at 12 weeks post-transplant we observed an abrogation of CD3+ cells derived from NR2F6 transduced T-cells (with the percentage of NR2F6 transduced CD3+ cells being comparable to staining with IgG control) in both the thymus and periphery. This stark competitive disadvantage was observed in all recipients of NR2F6 transduced grafts. We confirmed that this is not a phenomenon specific to the marker CD3 by analysing a portion of the animals for expression of CD4 and CD8, which again showed a lack of mature t-cells. In a second series of bone marrow transplants, cells transduced with NR2F6 or GFP were purified by fluorescence-activated cell sorting and grafts of 100% transduced cells were transferred by tail vein injection into lethally irradiated recipients. Animals transplanted with NR2F6 transduced bone marrow demonstrated a gross decrease in their thymic size and cellularity (∼10 fold decrease, n=17). Furthermore, the thymus of NR2F6 transduced animals contained a larger proportion of non-transduced, GFP negative residual haematopoietic cells than the vector control animals, corroborating the competitive disadvantage that NR2F6 transduced bone marrow cells face in the thymus. As observed in our previous experiments these animals demonstrated a gross reduction in the proportion of CD3+ cells in the thymus, spleen, lymph nodes and peripheral blood. To rule out the possibility that over-expression of NR2F6 is preventing the trafficking of progenitor cells to the thymus we differentiated NR2F6 or GFP transduced haematopoietic stem cells (lin-,c-kit+,sca-1+) into T-cells in vitro on OP9-DL1 cells. We observed a drastic reduction in the number of cells generated from NR2F6 transduced stem/progenitor cells (>50 fold at day 23), suggesting that expression of NR2F6 greatly impairs T-cell development. Mechanistically, others have shown that NR2F6 functions as a transcriptional repressor inhibiting the transactivating ability of genes such as Runx1. We conjecture that in lymphoid progenitors as well NR2F6 functions as a transcriptional repressor preventing the activation of pathways necessary for T-cell survival, proliferation and lymphopoiesis. Taken together, these data establish that the orphan nuclear receptor NR2F6 is a novel negative regulator of T-cell lymphopoiesis, and demonstrate that down-regulation of NR2F6 is important for the survival and proliferation of T-cell progenitors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions

2019 ◽  
Vol 5 (7) ◽  
pp. eaav9732 ◽  
Author(s):  
Carina Seitz ◽  
Juan Huang ◽  
Anna-Lena Geiselhöringer ◽  
Pamela Galbani-Bianchi ◽  
Svenja Michalek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nuclear Receptor ◽  
Transcriptional Control ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Orphan Nuclear Receptor ◽  
Cell Functions

LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation. T cell–specific deletion of LRH-1 causes a drastic loss of mature peripheral T cells. LRH-1–depleted CD4+ T cells exert strongly reduced activation-induced proliferation in vitro and in vivo and fail to mount immune responses against model antigens and to induce experimental intestinal inflammation. Similarly, LRH-1–deficient cytotoxic CD8+ T cells fail to control viral infections. This study describes a novel and critical role of LRH-1 in T cell maturation, functions, and immopathologies and proposes LRH-1 as an emerging pharmacological target in the treatment of T cell–mediated inflammatory diseases.

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

2021 ◽  
Vol 9 (4) ◽  
pp. e001937
Author(s):  
Jiayi Zhou ◽  
Xiaojuan Pei ◽  
Yingui Yang ◽  
Zhu Wang ◽  
Weijie Gao ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Cellular Localization ◽  
Immune Therapy ◽  
Gene Set Enrichment Analysis ◽  
Luciferase Reporter ◽  
Clinicopathological Parameters ◽  
Orphan Nuclear Receptor ◽  
Immune Microenvironment ◽  
Genome Atlas

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.

scholarly journals Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Laura M. Williamson ◽  
Craig M. Rive ◽  
Daniela Di Francesco ◽  
Emma Titmuss ◽  
Hye-Jung E. Chun ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Response ◽  
Immune Checkpoint ◽  
Treatment Options ◽  
Cell Receptor ◽  
Tumour Microenvironment ◽  
Whole Genome ◽  
Correlative Analysis ◽  
Genome Bisulfite Sequencing ◽  
Poorly Differentiated

AbstractPoorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the molecular and immune tumour microenvironment profiles of two paediatric PDCs produced using whole-genome, transcriptome and whole-genome bisulfite sequencing (WGBS) and multiplex immunohistochemistry. Our analyses revealed the presence of tumour-associated immune cells, including CD8+ T cells, and expression of the immune checkpoint protein, PD-L1, in both patient samples. Molecular profiling provided the rationale for immune checkpoint inhibitor (ICI) therapy, which resulted in a clinical and radiographic response. A dominant T cell receptor (TCR) clone specific for a brachyury peptide–MHC complex was identified from bulk RNA sequencing, suggesting that targeting of the brachyury tumour antigen by tumour-associated T cells may underlie this clinical response to ICI. Correlative analysis with rhabdoid tumours, another INI1-deficient paediatric malignancy, suggests that a subset of tumours may share common immune phenotypes, indicating the potential for a therapeutically targetable subgroup of challenging paediatric cancers.

scholarly journals Targeted Desialylation Overcomes Glyco-Immune Checkpoints and Potentiates the Anticancer Immune Response in Vivo

2019 ◽  
Author(s):  
Melissa Gray ◽  
Michal A. Stanczak ◽  
Han Xiao ◽  
Johan F. A. Pijnenborg ◽  
Stacy A. Malaker ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Therapy ◽  
Treatment Options ◽  
Immune Checkpoints ◽  
Alternative Pathways ◽  
Her2 Breast Cancer

<div><div><div><p>Currently approved immune checkpoint inhibitor (ICI) therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, the majority of patients across cancer types still fail to respond. Addressing alternative pathways that mediate immune suppression could enhance ICI efficacy. One such mechanism is the increase in sialic acid-containing proteins and lipids (sialoglycans) in malignancy, which recently has been shown to inhibit immune cell activation through multiple mechanisms including Siglec receptor binding, and therefore represents a targetable glyco-immune checkpoint. Here, we report the design of a trastuzumab- sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells in vivo. In a syngeneic orthotopic HER2+ breast cancer model, targeted desialylation delayed tumor growth and enhanced immune cell infiltration and activation, leading to prolonged survival of mice with trastuzumab-resistant breast cancer. Thus, antibody-sialidase conjugates represent a promising modality for cancer immune therapy.</p></div></div></div>

scholarly journals Role of NK Cells in Cancer and Immunotherapy

Onco ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 158-175
Author(s):  
Paresh Vishwasrao ◽  
Susanta K. Hui ◽  
D. Lynne Smith ◽  
Vishal Khairnar
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Treatment Options ◽  
Oncology Research ◽  
Cell Immunotherapy ◽  
Car T ◽  
Knowledge Of Cancer

Increasing knowledge of cancer immunology has led to the design of therapies using immune cells directly or manipulating their activity, collectively termed immunotherapy. In the field of immuno-oncology, research on adaptive immune T cells has led to the development of CAR-T cells. Innate immune cells such as NK cells can also eliminate oncogenically transformed cells and regulate cells of the immune system. Considering NK cells as a live drug, numerous methods for the isolation and activation of NK cells have been shown to be clinically and therapeutically relevant. In such processes, various cytokines and antibodies present a source of stimulation of NK cells and enhance the efficacy of such treatments. The ex vivo expansion and activation of NK cells, along with genetic modification with CAR, enhance their antitumor activity. Recent preclinical studies have shown an antitumor effect through extracellular vesicles (EVs) derived from NK cells. Work with autologous NK cells has provided insights for clinical applications. In this review, we outline the recent advances of NK-cell-based immunotherapies, summarizing CAR-NK cells, BiKEs, and TriKEs as treatment options against cancer. This review also discusses the challenges of NK cell immunotherapy.

scholarly journals Early programming of CD8+ T cell response by the orphan nuclear receptor NR4A3

2020 ◽  
Vol 117 (39) ◽  
pp. 24392-24402 ◽  
Author(s):  
Livia Odagiu ◽  
Salix Boulet ◽  
Dave Maurice De Sousa ◽  
Jean-François Daudelin ◽  
Sandrine Nicolas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Nuclear Receptor ◽  
T Cell Activation ◽  
Cell Response ◽  
Adoptive Cell Therapy ◽  
T Cell Response ◽  
Orphan Nuclear Receptor ◽  
T Cell Therapy

Enhancing long-term persistence while simultaneously potentiating the effector response of CD8+ T cells has been a long-standing goal in immunology to produce better vaccines and adoptive cell therapy products. NR4A3 is a transcription factor of the orphan nuclear receptor family. While it is rapidly and transiently expressed following T cell activation, its role in the early stages of T cell response is unknown. We show that NR4A3-deficient murine CD8+ T cells differentiate preferentially into memory precursor and central memory cells, but also produce more cytokines. This is explained by an early influence of NR4A3 deficiency on the memory transcriptional program and on accessibility of chromatin regions with motifs for bZIP transcription factors, which impacts the transcription of Fos/Jun target genes. Our results reveal a unique and early role for NR4A3 in programming CD8+ T cell differentiation and function. Manipulating NR4A3 activity may represent a promising strategy to improve vaccination and T cell therapy.

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