Beyond CTLA-4 and PD-1: Orphan nuclear receptor NR2F6 as T cell signaling switch and emerging target in cancer immunotherapy

Immunol Lett. 2016 Oct;178:31-6. doi: 10.1016/j.imlet.2016.03.007. Epub 2016 Mar 15.


Blockade of immune checkpoints has emerged as key strategy in the development of effective cancer therapies. In contrast to cell surface checkpoints like CTLA-4 and PD-1, however, additional cancer therapeutic targets are located inside the effector immune cells. Targeting these alternative checkpoints in cancer immunotherapy with the goal to strengthen the patient's immune system are likely to extend the benefits of cancer immunotherapy in the near future. Along this line, we have defined and validated the orphan nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) as an intracellular immune checkpoint in effector T cells. NR2F6 acts as a novel master switch of antitumor responses against both transplantable and spontaneous tumors in mice relevant for human cancer. NR2F6 directly represses transcription of key cytokine genes in T effector cells relevant for tumor cell rejection, such as IL-2, IFN and TNFα. Thus, in the presence of NR2F6, T cell activation is limited within the tumor microenvironment. This defines NR2F6 as a key checkpoint governing the amplitude of cancer immune surveillance. Based on our study, an approach shall be initiated to identify low molecular weight compounds that selectively interfere with NR2F6 function in the clinic.

Keywords: Intracellular and druggable cancer immune checkpoint; Orphan nuclear receptor NR2F6; Transcriptional cytokine gene repressor.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology*
  • CTLA-4 Antigen / metabolism*
  • Gene Expression Regulation
  • Humans
  • Immunomodulation
  • Immunotherapy / methods
  • Molecular Targeted Therapy
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / therapy
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / metabolism*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Repressor Proteins
  • Signal Transduction
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*


  • Antineoplastic Agents, Immunological
  • CTLA-4 Antigen
  • NR2F6 protein, human
  • Orphan Nuclear Receptors
  • Programmed Cell Death 1 Receptor
  • Receptors, Steroid
  • Repressor Proteins