PGE2, an anti-inflammatory prostaglandin

Prostaglandin E2 or PGE2 is a natural prostaglandin involved in inflammatory processes and is the ligand of the EP4 receptor ( EP4R ) GPCR. PGE2 is a metabolite of arachidonic acid via the action of PLA2 and COX enzymes. The latter can be found in two forms, COX-1 and COX-2. COX-1 is generally more ubiquitously found in the body whereas COX-2 is considered as an inducible enzyme whose expression is increased under pathological conditions. PGE2 is a key mediator of inflammation explaining the long development history of COX inhibitors as anti – inflammatory drugs . PGE2 prostaglandin acts by activating four distinct GPCRs termed EP1R, EP2R, EP3R and EP4R differing in tissue distribution and activated signalling pathways.

 

PGE2, an immunosuppressor prostaglandin

Like many others, the COX-2-PGE2 inflammatory pathway is highjacked by many solid tumors to shut down the natural anti-cancer immune response. Indeed, a COX-2 overexpression was already mentioned in multiple solid cancers, and the levels of PGE2 or its urine metabolite PGEM were reported to be more elevated in tumor paradigms. PGE2 is involved in the exhaustion of anti-tumor Tcells, in cancer cell invasiveness and in angiogenesis. This key immunosuppressive role of PGE2 is demonstrated in preclinical studies where COX-2 inhibitors were able to improve antitumor immunity of immune checkpoint inhibitors, but also in epidemiologic studies showing a reduction of cancer risk in population treated with COX inhibitors. Thus the PGE2 – EP4R constitute a strategic metabolic checkpoint axis to target using SME approach to bypass such immunosuppressive pathway.