Melanoma-intrinsic NR2F6 activity regulates anti-tumor immunity

Abstract

Nuclear receptors (NRs) have been implicated in tumor and immune cell regulation, most notably in hormone-dependent cancers. Here we identify a tumor-intrinsic function of the orphan nuclear receptor NR2F6 in regulating anti-tumor immunity. We selected NR2F6 among 48 candidate NRs based on an expression pattern in melanoma patient specimens coinciding with the IFN{gamma} signature, which is associated with positive responses to immunotherapy and favorable patient outcomes. Further delay of melanoma development was achieved upon combination of NR2F6 inhibition with anti-PD1 therapy. NR2F6 loss in B16F10 and YUMM1.7 melanoma cells attenuated tumor development in immune-competent but not -incompetent mice via increased CD8+ T cell infiltration and activation. Inhibition of NACC1 and FKBP10, identified here as NR2F6 effectors, phenocopied NR2F6 loss. Remarkably, inoculation of NR2F6 KD melanoma cells into mice genetically deficient in NR2F6 further enhanced tumor growth inhibition. Identifying a tumor-intrinsic function of NR2F6 which complements its tumor-extrinsic role could be thus exploited to develop novel anti-cancer therapies.