The COX2 Effector Microsomal PGE2 Synthase 1 is a Regulator of Immunosuppression in Cutaneous Melanoma.

Abstract

Microsomal prostaglandin E2 synthase 1 (mPGES1) was evaluated as an important downstream effector of the COX2 pathway responsible for tumor-mediated immunosuppression in melanoma. The analysis of a stage III melanoma tissue microarray (<i>n</i> = 91) was performed to assess the association between mPGES1, COX2, CD8, and patient survival. Pharmacologic inhibitors and syngeneic mouse models using <i>PTGES</i>-knockout (KO) mouse melanoma cell lines were used to evaluate the mPGES1-mediated immunosuppressive function. We observed correlations in expression and colocalization of COX2 and mPGES1, which are associated with increased expression of immunosuppressive markers in human melanoma. In a syngeneic melanoma mouse model, <i>PTGES</i> KO increased melanoma expression of PD-L1, increased infiltration of CD8a⁺ T cells, and CD8a⁺ dendritic cells into tumors and suppressed tumor growth. Durable tumor regression was observed in mice bearing <i>PTGES</i> KO 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 a shorter patient survival. Our results are the first to illustrate a potential role for mPGES1 inhibition in melanoma immune evasion and selective targeting in supporting the durability of response to PD-1 checkpoint immunotherapy. More research effort in this drug development space is needed to validate the use of mPGES1 inhibitors as safe treatment options.