The most successful strategies for solid cancer immunotherapy have centered on targeting the co-stimulatory and co-inhibitory T cell molecules that regulate T cell activation. Although immunotherapy that targets surface receptors such as CTLA-4 and/or PD-1 with recombinant antibodies has been a game changer for cancer treatment, a sizeable subset of patients still fail to respond to, and even fewer patients are cured by, these therapy regimens. The identification of alternate and potentially additive immune checkpoint candidates is intended to improve immunotherapies for a large number of cancer patients. Therefore, we focused on checkpoints located inside immune cells as suitable targets for future cancer drugs. We demonstrated, in recent years, the crucial T lymphocyte-intrinsic role of the orphan nuclear receptor NR2F6 as an intracellular checkpoint in fine-tuning adaptive immunity. NR2F6 induced an anti-inflammatory signal in the T cell compartment.
Cancer Type | Expression of NR2F6 | Role of NR2F6 | Ref |
---|---|---|---|
Leukemia | upregulated in patients | elevated population of LT-HSC | [41] |
Hepatocellular carcinoma | upregulated in patients | NR2F6 induces proliferation and metastasis via circRHOT1 and TIP60 | [38] |
Colon carcinoma | upregulated in patients | Nr2f6 increases survivability via XIAP | [39] |
Cervical cancer | upregulated in patients | correlation between metastasis, poor prognosis and NR2F6 expression | [42] |
Ovarian cancer | upregulated in patients | DDA1 is induced by NR2F6 and predicts poor outcome | [43][44] |
Breast cancer | upregulated in patients | n.d. | [45][46] |
Lung cancer | upregulated in patients | MiR-142-3p inhibits proliferation, migration and invasion via NR2F6 inhibition | [47] |
Effector T cells (mo and hu) | upregulated upon stimulation | transcriptional repressor directly antagonizing key cytokine gene loci | [40][48][49][50] |
Macrophages (mo) | n.d. | transcriptional repressor of cytokines | [51] |
Macrophages (hu) | n.d. | transcriptional activator of chemokines | [51] |
Tumor cells | upregulated | important for proliferation, metastasis, survivability | [38][39][42][47][52] |
Neurons (locus coeruleus) | n.d. | control of circadian clock | [53] |
Hepatocytes (mo and hu) | upregulated | hepatic steatosis promoted by NR2F6 | [54] |
Kidney | n.d. | NR2F6 as a negative regulator of renin gene transcription | [55] |
This entry is adapted from the peer-reviewed paper 10.3390/cancers13112600