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Article: Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6.

Klepsch, Victoria / Siegmund, Kerstin / Baier, Gottfried

2021 Volume 13, Issue 11

Abstract: Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside effector ... ...

Abstract	Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside effector CD4
Language	English
Publishing date	2021-05-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13112600
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Article ; Online: A MLR-Based Approach to Analyze Regulators of T Lymphocyte Activation In Vivo.

Koutník, Jiří / Klepsch, Victoria / Pommermayr, Maria / Thuille, Nikolaus / Baier, Gottfried / Siegmund, Kerstin

International journal of molecular sciences

2022 Volume 23, Issue 10

Abstract: Depending on the context, robust and durable T lymphocyte activation is either desirable, as in the case of anti-tumor responses, or unwanted, in cases of autoimmunity when chronic stimulation leads to self-tissue damage. Therefore, reliable in vivo ... ...

Abstract	Depending on the context, robust and durable T lymphocyte activation is either desirable, as in the case of anti-tumor responses, or unwanted, in cases of autoimmunity when chronic stimulation leads to self-tissue damage. Therefore, reliable in vivo models are of great importance to identify and validate regulatory pathways of T lymphocyte activation. Here, we describe an in vivo mixed-lymphocyte-reaction (MLR) approach, which is based on the so-called parent-into-F1 (P → F1) mouse model in combination with the congenic marker CD45.1/2 and cell proliferation dye-labeling. This setup allows us to track adoptively transferred allogenic CD4
MeSH term(s)	Animals ; Lymphocyte Activation ; Lymphocyte Culture Test, Mixed ; Mice ; Spleen ; T-Lymphocytes
Language	English
Publishing date	2022-05-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23105337
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Article ; Online: Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy.

Klepsch, Victoria / Pommermayr, Maria / Humer, Dominik / Brigo, Natascha / Hermann-Kleiter, Natascha / Baier, Gottfried

Cell communication and signaling : CCS

2020 Volume 18, Issue 1, Page(s) 8

Abstract: Background: NR2F6 has been proposed as an alternative cancer immune checkpoint in the effector T cell compartment. However, a realistic assessment of the in vivo therapeutic potential of NR2F6 requires acute depletion.: Methods: Employing primary T ... ...

Abstract	Background: NR2F6 has been proposed as an alternative cancer immune checkpoint in the effector T cell compartment. However, a realistic assessment of the in vivo therapeutic potential of NR2F6 requires acute depletion. Methods: Employing primary T cells isolated from Cas9-transgenic mice for electroporation of chemically synthesized sgRNA, we established a CRISPR/Cas9-mediated acute knockout protocol of Nr2f6 in primary mouse T cells. Results: Analyzing these Nr2f6 Conclusions: These findings indicate that Nr2f6
MeSH term(s)	Animals ; Base Sequence ; CRISPR-Cas Systems/genetics ; CTLA-4 Antigen/metabolism ; Cells, Cultured ; Gene Deletion ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Immunity/drug effects ; Mice, Inbred C57BL ; Mutagenesis/genetics ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/pathology ; Programmed Cell Death 1 Receptor/metabolism ; RNA, Guide, CRISPR-Cas Systems/metabolism ; Repressor Proteins/deficiency ; Repressor Proteins/metabolism ; Reproducibility of Results ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology
Chemical Substances	CTLA-4 Antigen ; Immune Checkpoint Inhibitors ; Nr2f6 protein, mouse ; Programmed Cell Death 1 Receptor ; RNA, Guide, CRISPR-Cas Systems ; Repressor Proteins
Language	English
Publishing date	2020-01-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-019-0454-z
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Article ; Online: Loss of the orphan nuclear receptor NR2F6 enhances CD8

Jakic, Bojana / Olson, William J / Siegmund, Kerstin / Klepsch, Victoria / Kimpel, Janine / Labi, Verena / Zehn, Dietmar / Baier, Gottfried / Hermann-Kleiter, Natascha

Cell death & disease

2021 Volume 12, Issue 2, Page(s) 187

Abstract: Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, ... ...

Abstract	Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127
Language	English
Publishing date	2021-02-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-021-03470-9
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Article ; Online: Beyond CTLA-4 and PD-1: Orphan nuclear receptor NR2F6 as T cell signaling switch and emerging target in cancer immunotherapy.

Klepsch, Victoria / Hermann-Kleiter, Natascha / Baier, Gottfried

Immunology letters

2016 Volume 178, Page(s) 31–36

Abstract: Blockade of immune checkpoints has emerged as key strategy in the development of effective cancer therapies. In contrast to cell surface checkpoints like CTLA-4 and PD-1, however, additional cancer therapeutic targets are located inside the effector ... ...

Abstract	Blockade of immune checkpoints has emerged as key strategy in the development of effective cancer therapies. In contrast to cell surface checkpoints like CTLA-4 and PD-1, however, additional cancer therapeutic targets are located inside the effector immune cells. Targeting these alternative checkpoints in cancer immunotherapy with the goal to strengthen the patient's immune system are likely to extend the benefits of cancer immunotherapy in the near future. Along this line, we have defined and validated the orphan nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) as an intracellular immune checkpoint in effector T cells. NR2F6 acts as a novel master switch of antitumor responses against both transplantable and spontaneous tumors in mice relevant for human cancer. NR2F6 directly represses transcription of key cytokine genes in T effector cells relevant for tumor cell rejection, such as IL-2, IFN and TNFα. Thus, in the presence of NR2F6, T cell activation is limited within the tumor microenvironment. This defines NR2F6 as a key checkpoint governing the amplitude of cancer immune surveillance. Based on our study, an approach shall be initiated to identify low molecular weight compounds that selectively interfere with NR2F6 function in the clinic.
MeSH term(s)	Animals ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Agents, Immunological/therapeutic use ; CTLA-4 Antigen/antagonists & inhibitors ; CTLA-4 Antigen/immunology ; CTLA-4 Antigen/metabolism ; Gene Expression Regulation ; Humans ; Immunomodulation ; Immunotherapy/methods ; Molecular Targeted Therapy ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/therapy ; Orphan Nuclear Receptors/genetics ; Orphan Nuclear Receptors/metabolism ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/metabolism ; Receptors, Steroid/genetics ; Receptors, Steroid/metabolism ; Repressor Proteins ; Signal Transduction ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Antineoplastic Agents, Immunological ; CTLA-4 Antigen ; NR2F6 protein, human ; Orphan Nuclear Receptors ; Programmed Cell Death 1 Receptor ; Receptors, Steroid ; Repressor Proteins
Language	English
Publishing date	2016-03-15
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	445150-8
ISSN	1879-0542 ; 0165-2478
ISSN (online)	1879-0542
ISSN	0165-2478
DOI	10.1016/j.imlet.2016.03.007
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Article ; Online: Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD.

Klepsch, Victoria / Moschen, Alexander R / Tilg, Herbert / Baier, Gottfried / Hermann-Kleiter, Natascha

Frontiers in immunology

2019 Volume 10, Page(s) 1070

Abstract: Gastrointestinal (GI) homeostasis is strongly dependent on nuclear receptor (NR) functions. They play a variety of roles ranging from nutrient uptake, sensing of microbial metabolites, regulation of epithelial intestinal cell integrity to shaping of the ... ...

Abstract	Gastrointestinal (GI) homeostasis is strongly dependent on nuclear receptor (NR) functions. They play a variety of roles ranging from nutrient uptake, sensing of microbial metabolites, regulation of epithelial intestinal cell integrity to shaping of the intestinal immune cell repertoire. Several NRs are associated with GI pathologies; therefore, systematic analysis of NR biology, the underlying molecular mechanisms, and regulation of target genes can be expected to help greatly in uncovering the course of GI diseases. Recently, an increasing number of NRs has been validated as potential drug targets for therapeutic intervention in patients with inflammatory bowel disease (IBD). Besides the classical glucocorticoids, especially PPARγ, VDR, or PXR-selective ligands are currently being tested with promising results in clinical IBD trials. Also, several pre-clinical animal studies are being performed with NRs. This review focuses on the complex biology of NRs and their context-dependent anti- or pro-inflammatory activities in the regulation of gastrointestinal barrier with special attention to NRs already pharmacologically targeted in clinic and pre-clinical IBD treatment regimens.
MeSH term(s)	Gastrointestinal Microbiome/physiology ; Homeostasis ; Humans ; Inflammatory Bowel Diseases/drug therapy ; Inflammatory Bowel Diseases/etiology ; PPAR gamma/physiology ; Pregnane X Receptor/physiology ; Receptors, Calcitriol/physiology ; Receptors, Cytoplasmic and Nuclear/drug effects ; Receptors, Cytoplasmic and Nuclear/physiology
Chemical Substances	PPAR gamma ; Pregnane X Receptor ; Receptors, Calcitriol ; Receptors, Cytoplasmic and Nuclear
Language	English
Publishing date	2019-05-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.01070
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Article ; Online: Loss-of-function phenotype of a PKCθ

Thuille, Nikolaus / Siegmund, Kerstin / Klepsch, Victoria / Schörgenhuber, Jacqueline / Danklmaier, Sarah / Leitges, Michael / Baier, Gottfried

Cell communication and signaling : CCS

2019 Volume 17, Issue 1, Page(s) 141

Abstract: Background: Protein kinase C θ has been established as an important signaling intermediate in T-effector-cell activation and survival pathways by controlling activity of the key transcription factors NF-κB and NFAT. Previous studies identified an ... ...

Abstract	Background: Protein kinase C θ has been established as an important signaling intermediate in T-effector-cell activation and survival pathways by controlling activity of the key transcription factors NF-κB and NFAT. Previous studies identified an activation-induced auto-phosphorylation site at Thr-219, located between the tandem C1 domains of the regulatory fragment in PKCθ, as a structural requirement for its correct membrane translocation and the subsequent transactivation of downstream signals leading to IL-2 production in a human T cell line. Methods: The present work aimed to define the role of this phosphorylation switch on PKCθ in a physiological context through a homozygous T219A knockin mouse strain. T cell activation was analyzed by H3-thymidine uptake (proliferative response), qRT-PCR and luminex measurements (cytokine production). NFAT and NF-κB transactivation responses were estimated by Gel mobility shift and Alpha Screen assays. Frequencies of T cell subsets were analyzed by flow cytometry. Results: Despite a normal T cell development, in vitro activated effector T cells clearly revealed a requirement of Thr-219 phosphorylation site on PKCθ for a transactivation of NF-κB and NFAT transcription factors and, subsequently, robust IL-2 and IFN-γ expression. Conclusion: This phenotype is reminiscent of the PKCθ knockout T cells, physiologically validating that this (p) Thr-219 auto-phosphorylation site indeed critically regulates PKCθ function in primary mouse T cells.
MeSH term(s)	Animals ; Cytokines/metabolism ; Gene Knock-In Techniques ; Mice ; Phenotype ; Protein Kinase C-theta/genetics ; Protein Kinase C-theta/metabolism ; T-Lymphocytes/cytology ; T-Lymphocytes/metabolism
Chemical Substances	Cytokines ; Protein Kinase C-theta (EC 2.7.11.13)
Language	English
Publishing date	2019-11-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1478-811X
ISSN (online)	1478-811X
DOI	10.1186/s12964-019-0466-8
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Article ; Online: Melanoma-intrinsic NR2F6 activity regulates antitumor immunity.

Kim, Hyungsoo / Feng, Yongmei / Murad, Rabi / Pozniak, Joanna / Pelz, Carl / Chen, Yeqing / Dalal, Bhavik / Sears, Rosalie / Sergienko, Eduard / Jackson, Michael / Ruppin, Eytan / Herlyn, Meenhard / Harris, Curtis / Marine, Jean-Christophe / Klepsch, Victoria / Baier, Gottfried / Ronai, Ze'ev A

Science advances

2023 Volume 9, Issue 27, Page(s) eadf6621

Abstract: 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 antitumor immunity. NR2F6 was selected from 48 candidate NRs based on an expression pattern in ...

Abstract	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 antitumor immunity. NR2F6 was selected from 48 candidate NRs based on an expression pattern in melanoma patient specimens (i.e., IFN-γ 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
MeSH term(s)	Animals ; Mice ; CD8-Positive T-Lymphocytes ; Immunotherapy ; Melanoma/genetics ; Repressor Proteins/metabolism
Chemical Substances	Repressor Proteins ; Nr2f6 protein, mouse
Language	English
Publishing date	2023-07-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adf6621
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Article ; Online: Proof of Principle for a T Lymphocyte Intrinsic Function of Coronin 1A.

Siegmund, Kerstin / Klepsch, Victoria / Hermann-Kleiter, Natascha / Baier, Gottfried

The Journal of biological chemistry

2016 Volume 291, Issue 42, Page(s) 22086–22092

Abstract: Coronins are evolutionarily conserved proteins that were originally identified as modulators of actin-dependent processes. Studies analyzing complete Coronin 1a knock-out mice have shown that this molecule is an important regulator of naive T cell ... ...

Abstract	Coronins are evolutionarily conserved proteins that were originally identified as modulators of actin-dependent processes. Studies analyzing complete Coronin 1a knock-out mice have shown that this molecule is an important regulator of naive T cell homeostasis and it has been linked to immune deficiencies as well as autoimmune disorders. Nevertheless, because Coronin 1A is strongly expressed in all leukocyte subsets, it is not conclusive whether or not this phenotype is attributed to a T cell-intrinsic function of Coronin 1A. To address this research question, we have generated a T cell-specific Coronin 1a knock-out mouse (Coro1a
MeSH term(s)	Animals ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/pathology ; Encephalomyelitis, Autoimmune, Experimental/genetics ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/pathology ; Immunologic Memory ; Mice ; Mice, Knockout ; Microfilament Proteins/genetics ; Microfilament Proteins/immunology ; Multiple Sclerosis/genetics ; Multiple Sclerosis/immunology ; Multiple Sclerosis/pathology
Chemical Substances	Microfilament Proteins ; coronin proteins (145420-64-0)
Language	English
Publishing date	2016-08-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.748012
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Article ; Online: Orphan Nuclear Receptor NR2F6 Suppresses T Follicular Helper Cell Accumulation through Regulation of IL-21.

Olson, William J / Jakic, Bojana / Labi, Verena / Schoeler, Katia / Kind, Michaela / Klepsch, Victoria / Baier, Gottfried / Hermann-Kleiter, Natascha

Cell reports

2019 Volume 28, Issue 11, Page(s) 2878–2891.e5

Abstract: CD4 T follicular helper (Tfh) cells are specialized in helping B cells during the germinal center (GC) reaction and ultimately promote long-term humoral immunity. Here we report that loss of the nuclear orphan receptor NR2F6 causes enhanced survival and ... ...

Abstract	CD4 T follicular helper (Tfh) cells are specialized in helping B cells during the germinal center (GC) reaction and ultimately promote long-term humoral immunity. Here we report that loss of the nuclear orphan receptor NR2F6 causes enhanced survival and accumulation of Tfh cells, GC B cells, and plasma cells (PCs) following T cell-dependent immunization. Nr2f6-deficient CD4 T cell dysfunction is the primary cause of cell accumulation. Cytokine expression in Nr2f6-deficient Tfh cells is dysregulated, and Il21 expression is enhanced. Mechanistically, NR2F6 binds directly to the interleukin 21 (IL-21) promoter and a conserved noncoding sequence (CNS) near the Il21 gene in resting CD4
MeSH term(s)	Adoptive Transfer ; Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cell Differentiation/immunology ; Cells, Cultured ; Chromatin Immunoprecipitation ; Germinal Center/cytology ; Germinal Center/immunology ; Interleukins/metabolism ; Lymphocyte Activation/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Orphan Nuclear Receptors/genetics ; Orphan Nuclear Receptors/metabolism ; Plasma Cells/immunology ; Promoter Regions, Genetic ; Receptors, Interleukin-21/metabolism ; Repressor Proteins/deficiency ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism
Chemical Substances	Interleukins ; Nr2f6 protein, mouse ; Orphan Nuclear Receptors ; Receptors, Interleukin-21 ; Repressor Proteins ; interleukin-21 (MKM3CA6LT1)
Language	English
Publishing date	2019-09-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.08.024
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