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

• Main Authors: Natascha Hermann-Kleiter, Victoria Klepsch, Stephanie Wallner, Kerstin Siegmund, Sebastian Klepsch, Selma Tuzlak, Andreas Villunger, Sandra Kaminski, Christa Pfeifhofer-Obermair, Thomas Gruber, Dominik Wolf, Gottfried Baier
• Format: Article
• Language: English
• Published: Elsevier 2015-09-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124715009201

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.