Key role of the positive feedback between PGE₂ and COX2 in the biology of myeloid-derived suppressor cells

Figures & data

Figure 1. Positive COX2-PGE₂-EP2/EP4-mediated feedback loop in the biology of cancer-associated MDSCs. Inflammation (IL-1β, TLR ligands, IFN-γ) and/or cancer-produced PGE₂ or PGE₂ inducers drive the early induction of COX2 in local myeloid cells (monocytes, macrophages, immature DCs), promoting their production of suppressive factors (IDO1, IL-10, ARG1, NOS2 and PGE₂ itself), and acquisition of suppressive functions. The EP2- and EP4-dependent signals are also critical in the induction and persistence of functional CXCR4 on monocytic cells and for the production of CXCL12/SDF-1 in cancer environment. These processes are further amplified by the de novo-produced endogenous PGE₂, now produced at high levels by MDSCs themselves, thereby creating a positive feedback loop, leading to accumulation of MDSCs in cancer environment. In addition to inducing other suppressive factors, PGE₂ also directly suppresses CTL development and functions, acting via EP2 and EP4 receptors. The key role of the EP2- and EP4-mediated COX2-PGE₂ feedback to control multiple aspects of MDSC function provides for convenient targets to control MDSC-associated immune dysfunction in cancer immunotherapy.