Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade

Abstract

Analyzing mouse tumor models in vivo, human T cells ex vivo, and human lung cancer samples, we provide direct evidence that NR2F6 acts as an immune checkpoint. Genetic ablation of Nr2f6, particularly in combination with established cancer immune checkpoint blockade, efficiently delays tumor progression and improves survival in experimental mouse models. The target genes deregulated in intratumoral T lymphocytes upon genetic ablation of Nr2f6 alone or together with PD-L1 blockade reveal multiple advantageous transcriptional alterations. Acute Nr2f6 silencing in both mouse and human T cells induces hyper-responsiveness that establishes a non-redundant T-cell-inhibitory function of NR2F6. NR2F6 protein expression in T-cell-infiltrating human NSCLC is upregulated in 54% of the cases (n = 303) and significantly correlates with PD-1 and CTLA-4 expression. Our data define NR2F6 as an intracellular immune checkpoint that suppresses adaptive anti-cancer immune responses and set the stage for clinical validation of targeting NR2F6 for next-generation immuno-oncological regimens.

Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway

“…These prior researches implied that NR2F6 might be closely involved in the pathophysiology of malignant diseases and may play a dual role in cancer progression. Our present results are in line with previous studies, which indicate that NR2F6 expression promotes the CSC phenotype and induces cisplatin resistance of ovarian cancer cells by positively regulating transcriptional activation of the Notch3 signaling pathway.…”

“…24 Previous studies have suggested that NR2F6 may function to positively regulate tumor cell survivability and to induce cancer progression. On the contrary, some reports have demonstrated that NR2F6 can act as a strong negative regulator for the function of the thyroid hormone (T3) nuclear receptor (TR), which regulates cell growth, differentiation and development 25 Notably, Victoria et al 9 reported that NR2F6 serves as safeguard to protect gut barrier homeostasis. Our knowledge of the maintenance of intestinal barrier homeostasis is dependent on the differentiation and maturation of stem cells from the intestinal recess.…”

“…Victoria et al demonstrated that NR2F6 acts as an intracellular immunity checkpoint and genetic ablation of NR2F6 acts as a "sensitizer" that enables improved therapeutic activity of clinically approved agents that block the PD-1/PD-L1 axis. 9 Thus, targeting NR2F6 appears to be a suitable strategy to enhance the efficacy of cancer immunotherapy. However, whether NR2F6 expression is directly correlated with tumor progression, especially in EOC, remains largely unclear.…”

Transcriptomic Features of T Cell-Barren Tumors Are Conserved Across Diverse Tumor Types

“…Consistent with this observation, NR2F6 has been documented to function as a gatekeeper of anti-tumor immunity through transcriptional repression of proinflammatory cytokines including IL-2, IFNγ, and TNFα (35,53). Furthermore, NR2F6 inhibition has been shown to augment the efficacy of ICB in preclinical prostate, melanoma, and colorectal cancer models, as well as increase tumor infiltration by IFNγ-positive T cells (35,54). However, an immunoevasive function for NR2F6 cancer-specific expression has not yet been described.…”

Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy

“…Our group identified the orphan nuclear receptor NR2F6 (nuclear receptor subfamily 2, group F, member 6; alias Ear2 and COUP-TFIII) as an intracellular immune checkpoint candidate fine-tuning adaptive immunity [25][26][27][28][29][30]. Nr2f6-deficient mice show an increased tendency for experimentally-induced neuroinflammation [25,26] as well as improved intratumoral effector T-cell response resulting in strongly decelerated tumor growth in different spontaneous as well as transplantable mouse tumor models [29,30]. Mechanistically, lymphatic NR2F6 acts as a negative-regulatory signaling intermediate downstream of the antigen receptor and sets the threshold of TCR/CD28 activation-induced effector functions by acting as a transcriptional repressor that directly antagonizes the DNA accessibility of activationinduced NFAT/AP-1 transcription factors at cytokine gene loci such as Il2 and Ifng [29,30].…”