Intrinsic Microsomal Pge2 Synthase-1 Associates With Poor Patient Survival And T-Cell Infiltration, And Regulates Immunosuppression In Human And Mouse Melanoma Models.

Our research has identified microsomal prostaglandin E2 synthase 1 (mPGES1) as an important downstream effector of the cyclooxygenase 2 (COX2) pathway often expressed by melanoma cells, and largely responsible for tumor-mediated immunosuppression. We observed clear correlations in expression and co-localization of COX2 and mPGES1, for which both are associated with increased expression of immunosuppressive markers in human melanoma. In a syngeneic melanoma mouse model, mPGES1 knockout increased melanoma expression of PD-L1 showing about 25% positive cells, increased infiltration of CD8a+ T cells (around 8 fold) and CD8a+ dendritic cells (around 10 fold) into tumors and suppressed tumor growth (around 70%). Durable tumor regression was observed in mice bearing mPGES1 knockout tumors that were given anti-PD-1 therapy. Analysis of a stage III melanoma tissue microarray revealed significant associations between high mPGES1 expression and low CD8+ infiltration, which correlated with poor survival. Collectively, our results are the first to illustrate a potential role for mPGES1-inhibition and selective targeting in melanoma immune evasion and in supporting the durability of response to PD-1 checkpoint immunotherapy. Research in the development of mPGES1 inhibitors is needed to validate their use as safe treatment options, but they appear attractive and feasible based on data to date. Citation Format: Sun-Hee Kim, Jason Roszik, Sungnam Cho, Dai Ogata, Suhendan Ekmekcioglu, Elizabeth A Grimm. Intrinsic microsomal PGE2 synthase-1 associates with poor patient survival and T-cell infiltration, and regulates immunosuppression in human and mouse melanoma models [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B13.