ROR alpha Regulates Cholesterol Metabolism of CD8(+) T Cells for Anticancer Immunity

Abstract

Retinoic acid-related orphan receptor alpha (ROR alpha) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that ROR alpha is crucial for maintaining cholesterol homeostasis in CD8(+)T cells by attenuating NF-kappa B transcriptional activity. Cholesterol sulfate, the established natural agonist of ROR alpha, exhibits cellular cytotoxicity on, and increased effector responses in, CD8(+)T cells. Transcript analysis reveals that the suppression of ROR alpha leads to the upregulation of NF-kappa B target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of ROR alpha and histone deacetylase (HDAC) on NF-kappa B target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that ROR alpha/HDAC-mediated attenuation of NF-kappa B signaling controls the balance of cholesterol metabolism in CD8(+)T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.