Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

• Main Authors: Victoria Klepsch, Kerstin Siegmund, Gottfried Baier
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Cancers
• Subjects: tumor immunology; orphan nuclear receptor NR2F6; tumor-promoting function; alternative and druggable cancer immune checkpoint; transcriptional repressor of CD4⁺ and CD8⁺ effector but not regulatory T cell functions; NR2F6 inhibition as first-in-class cancer immunotherapy concept
• Online Access: https://www.mdpi.com/2072-6694/13/11/2600

Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside effector CD4⁺ and CD8⁺ T cells. It is likely that future treatment options will combine surface receptor and intracellular protein targets. Utilizing germline gene ablation as well as CRISPR/Cas9-mediated acute gene mutagenesis, the nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) has been firmly characterized as such an intracellular immune checkpoint in effector T cells. Targeting this receptor appears to be a strategy for improving anti-tumor immunotherapy responses, especially in combination with CTLA-4 and PD-1. Current preclinical experimental knowledge firmly validates the immune checkpoint function of NR2F6 in murine tumor models, which provides a promising perspective for immunotherapy regimens in humans in the near future. While the clinical focus remains on the B7/CD28 family members, protein candidate targets such as NR2F6 are now being investigated in laboratories around the world and in R&D companies. Such an alternative therapeutic approach, if demonstrated to be successful, could supplement the existing therapeutic models and significantly increase response rates of cancer patients and/or expand the reach of immune therapy regimens to include a wider range of cancer entities. In this perspective review, the role of NR2F6 as an emerging and druggable target in immuno-oncology research will be discussed, with special emphasis on the unique potential of NR2F6 and its critical and non-redundant role in both immune and tumor cells.