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Cell Rep. 2015 Sep 29;12(12):2072-85. doi: 10.1016/j.celrep.2015.08.035. Epub 2015 Sep 17.

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

Author information

1
Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria. Electronic address: natascha.kleiter@i-med.ac.at.
2
Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
3
Laboratory of Tumor Immunology, Tyrolean Cancer Institute & Internal Medicine V, Medical University of Innsbruck, 6020 Innsbruck, Austria.
4
Division of Developmental Immunology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
5
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.
6
Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria. Electronic address: gottfried.baier@i-med.ac.at.

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.

PMID:
26387951
PMCID:
PMC4594157
DOI:
10.1016/j.celrep.2015.08.035
[Indexed for MEDLINE]
Free PMC Article

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