Abstract
<div>Abstract<p>The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2–derived PGE<sub>2</sub>, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4–PI3K–Akt signaling pathway in both CD8<sup>+</sup> T cells and macrophages. Moreover, PGE<sub>2</sub> suppresses CD8<sup>+</sup> T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4–PI3K–Akt–NFκB–PD-1 signaling pathway. In contrast, inhibiting the COX-2–PGE<sub>2</sub>–EP4 pathway increases intestinal CD8<sup>+</sup> T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8<sup>+</sup> T cells and macrophages in <i>Apc<sup>Min</sup></i><sup>/+</sup> mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE<sub>2</sub> in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion.</p>Prevention Relevance:<p>These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE<sub>2</sub> signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs.</p></div>
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