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

• Genetic ablation of Nr2f6 induces immune-mediated cancer surveillance
• Nr2f6−/− mice display an immune contexture favoring anti-tumor responses
• NR2F6 represses transcription of key cytokines in CD4+ and CD8+ effector T cells
• NR2F6 controls the amplitude of tumor immunity

SummaryNuclear 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.

Graphical AbstractFigure optionsDownload as PowerPoint slide