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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / transplantation
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • COUP Transcription Factors / deficiency
  • COUP Transcription Factors / genetics*
  • COUP Transcription Factors / immunology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunologic Memory
  • Immunologic Surveillance*
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / agonists
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-2 / agonists
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / mortality
  • Prostatic Neoplasms / therapy*
  • Repressor Proteins
  • Signal Transduction
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / agonists
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • COUP Transcription Factors
  • Interleukin-2
  • Nr2f6 protein, mouse
  • Repressor Proteins
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma