284P TES-4207, a first-in-class antagonist of the immune checkpoint NR2F6, drives anti-tumor immunity and enhances efficacy of PD-1 blockade

Anti-cancer immune checkpoint inhibitors (ICI) have low patient response rates, partly due to unelucidated resistance mechanisms. High expression of the orphan nuclear receptor NR2F6, a transcriptional repressor of key anti-tumor cytokines like IL-2 and IFNγ, has been identified as a biomarker for ICI resistance and correlates with a low IFNγ signature in melanoma. In T cells, NR2F6 limits immune infiltration and activation within the tumor microenvironment (TME). The lack of small molecule ligands has previously limited its evaluation as a drug target.