Nuclear Receptor NR2F6 as an Alternative Cancer Immune Checkpoint in the T Cell Compartment

Analyzing mouse tumor models in vivo, human T cells ex vivo and human lung cancer samples, we provide direct evidence that NR2F6 acts as novel immune checkpoint. Genetic ablation of Nr2f6, particularly in combination with blockade of the established PD-L1 cancer immune checkpoint, efficiently delayed tumor progression and improved 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, revealed multiple advantageous transcriptional alterations for effective tumor rejection. In keeping with the above observation, acute Nr2f6 silencing in both mouse and human T cells induced hyper-responsiveness that established a non-redundant T cell-inhibitory function of NR2F6. Analyzing mouse tumor models in vivo, human T cells ex vivo and human lung cancer samples, TILs derived from wild-type and Nr2f6-/- tumor-bearing mice collected at d14 after B16-OVA tumor cell injection. and subjected to detailed analysis, including FACS sequencing and RNA sequencing