The COX-2-PGE(2) Pathway Promotes Tumor Evasion in Colorectal Adenomas

The mechanisms underlying the regulation of a check-point 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(2), an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NF kappa B's binding to the PD-1 promoter via an EP4-PI3K-Akt signaling pathway in both CD8(+) T cells and macrophages. Moreover, PGE(2) suppresses CD8(+) T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4-PI3K-Akt-NFKB-PD-1 signaling pathway. In contrast, inhibiting the COX-2-PGE(2) -EP4 pathway increases intestinal CD8(+) T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8(+) T cells and macrophages in Apc(Min/+ )finl+ 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(2) 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.