title: The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance.
abstract: Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily. Here, we show that genetic ablation of Nr2f6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, Nr2f6(-/-) mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor rechallenge. This is paralleled by increased frequencies of both CD4(+) and CD8(+) T cells and higher expression levels of interleukin 2 and interferon γ at the tumor site. Mechanistically, CD4(+) and CD8(+) T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds. Adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity.
authors.affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria. Electronic address: natascha.kleiter@i-med.ac.at.
authors.forename: Natascha
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Victoria
authors.initials: V
authors.lastname: Klepsch
authors.affiliation: Laboratory of Tumor Immunology, Tyrolean Cancer Institute & Internal Medicine V, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wallner
authors.affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Siegmund
authors.affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Klepsch
authors.affiliation: Division of Developmental Immunology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Selma
authors.initials: S
authors.lastname: Tuzlak
authors.affiliation: Division of Developmental Immunology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kaminski
authors.affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Christa
authors.initials: C
authors.lastname: Pfeifhofer-Obermair
authors.affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruber
authors.affiliation: Laboratory of Tumor Immunology, Tyrolean Cancer Institute & Internal Medicine V, Medical University of Innsbruck, 6020 Innsbruck, Austria; Medical Clinic III, Oncology, Hematology & Rheumatology, University Clinic Bonn, 53127 Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria. Electronic address: gottfried.baier@i-med.ac.at.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D051836:COUP Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007156:Immunologic Memory; D007157:Immunologic Surveillance; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000819:agonists / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D012097:Repressor Proteins; D015398:Signal Transduction; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000235:genetics / Q000276:immunology
chemical_list: D051836:COUP Transcription Factors; D007376:Interleukin-2; C484221:Nr2f6 protein, mouse; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma