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Role of Nuclear Hormone Receptor Peroxisome Proliferator-Activated Receptor Delta in Colorectal Cancer


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Colorectal adenomas are the precursors of colorectal cancer (CRC). The key question is what allows benign adenomas to grow and to eventually become cancerous. Understanding the molecular mechanisms underlying colorectal adenoma formation and growth would offer tremendous opportunities for CRC prevention and interception. The nuclear hormone receptor PPARd is a transcription factor that is involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. However, the role of PPARd in colorectal adenoma biology and progression remains unclear. Particularly, the role of PPARd in tumor immune evasion is unknown. Since we found that both PD-1 and PD-L1 promoters contain potential PPARd binding sites and our preliminary in vitro data show that activation of PPARd induces PD-L1expression in colorectal tumor cells and PD-1 expression in CD8+ T cells and macrophages, we hypothesize that PPARd induction of PD-L1 in colon tumor epithelial cells induces their resistance to CD8+ T cell cytotoxicity (Aim 1) and activation of PPARd induces tumor immune evasion by suppressing colorectal CD8+ T cell cytotoxicity and inhibiting macrophage phagocytosis via induction of PD-1 (Aim 2). Since certain fatty acids and fatty acid derivatives are natural ligands of PPARd, we postulate that PPARd mediates the effect of dietary fats on PD-L1 in tumor cells andPD-1 in CD8+ T cells and macrophages. This proposal will provide a rationale for developing PPARd antagonists as agents to target immune checkpoint pathways and to enhance the efficacy of checkpoint inhibitors in treatment of CRC patients.



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