Defining the Transcriptional Regulation of NR2F6 in TH17 Cell Responses 4753

Abstract Description NR2F6 is an orphan nuclear receptor reported to repress pro-inflammatory cytokines IL-2, IL-17A, IL-21, and IFNγ. The cytokine modulatory effects of NR2F6 have demonstrated its potential as a therapeutic target for autoimmune and cancer indications. NR2F6 has been implicated as an intracellular checkpoint for cancer immune surveillance, and its deletion has been shown to potentiate PD-1/PD-L1 blockade in several cancer models. Our work aims to define the molecular mechanism responsible for these effects, so that NR2F6 can be better exploited as an immunotherapy target. Integrated RNAseq and CUT&RUN (Cleavage Under Targets and Release Using Nuclease) mapping in primary TH17 cells has identified genes involved in TNF signaling as direct targets of NR2F6. Among these genes is Tnfrsf9, whose decrease in transcript levels by RNAseq is accompanied by a decrease in chromatin accessibility, measured by ATACseq, and decreased surface expression of its protein product, CD137, measured by flow cytometry. Since transcription factors frequently work in concert, co-immunoprecipitation coupled with mass-spectrometry proteomics experiments have identified 8 potential transcription factor partners of NR2F6 in TH17 cells. Current work is ongoing to determine which of these, are potentially interacting with NR2F6 at the Tnfrsf9 locus. Together these data are unraveling the transcriptional network that NR2F6 orchestrates for therapeutic potential. Funding Sources NIH 1F31DK137613-01A1 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)