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ROR? Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity.

ABSTRACT: Retinoic acid-related orphan receptor ? (ROR?) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that ROR? is crucial for maintaining cholesterol homeostasis in CD8+ T cells by attenuating NF-kB transcriptional activity. Cholesterol sulfate, the established natural agonist of ROR?, exhibits cellular cytotoxicity on, and increased effector responses in, CD8+ T cells. Transcript analysis reveals that the suppression of ROR? leads to the upregulation of NF-kB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of ROR? and histone deacetylase (HDAC) on NF-kB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that ROR?/HDAC-mediated attenuation of NF-kB 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.

SUBMITTER: Lee IK

PROVIDER: S-EPMC7407186 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity.

Lee In Kyu IK Song Hyerin H Kim Hyerim H Kim Ik Soo IS Tran Na Ly NL Kim Sang-Heon SH Oh Seung Ja SJ Lee Ji Min JM

Cancers 20200629 7

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8+ T cells by attenuating NF-kB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8+ T cel ...[more]

PMID: 32610705

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Project description:BackgroundT cell-mediated antitumor immune response is the basis of colorectal cancer (CRC) immunotherapy. Cholesterol plays an important role in T cell signal transduction and function. Apolipoprotein E (APOE) plays a major role in cholesterol metabolism.ObjectiveTo screen and analyze key markers involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism.MethodsBased on the median cutoff of the expression value of APOE according to the data downloaded from The Cancer Genome Atlas and Gene Expression Omnibus database, patients were grouped into low and high expression groups. Differences in clinical factors were assessed, and survival analysis was performed. Differentially expressed genes (DEGs) in the high and low expression groups were screened, followed by the analysis of differences in tumor-infiltrating immune cells and weighted gene coexpression network analysis results. The closely related genes to APOE were identified, followed by enrichment analysis, protein-protein interaction (PPI) network analysis, and differential expression analysis. Immunohistochemical staining (IHC) was used to detect the expression of CD8 in CRC tissues.ResultsThere were significant differences in prognosis and pathologic_N between the APOE low and high expression groups. A total of 2,349 DEGs between the high and low expression groups were selected. A total of 967 genes were obtained from the blue and brown modules. The probability of distribution of CD8+ T cells differed significantly between the two groups, and 320 closely related DEGs of APOE were screened. Genes including the HLA gene family, B2M, IRF4, and STAT5A had a higher degree in the PPI network. GEO datasets verified the prognosis and the related DEGs of APOE. IHC staining verified the relationship between the distribution of CD8+ T cells and APOE expression.ConclusionGenes including the HLA gene family, B2M, IRF4, and STAT5A might be the key genes involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism.

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ROR? Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity.

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RORα Regulates Cholesterol Metabolism of CD8<sup>+</sup> T Cells for Anticancer Immunity.

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