The COX2 effector microsomal PGE2 synthase-1 is a regulator of immunosuppression in cutaneous melanoma

Purpose: Microsomal prostaglandin E2 synthase 1 (mPGES1) was evaluated as an important downstream effector of the cyclooxygenase 2 (COX2) pathway responsible for tumor-mediated immunosuppression in melanoma. Experimental Design: The analysis of a Stage III melanoma tissue microarray (n=91) was performed to assess the association between mPGES1, COX2, CD8, and patient survival. Pharmacological inhibitors and syngeneic mouse models using mPGES1 knockout mouse melanoma cell lines were used to evaluate the mPGES1-mediated immunosuppressive function. Results: We observed correlations in expression and co-localization of COX2 and mPGES1, which 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, increased infiltration of CD8a+ T cells and CD8a+ dendritic cells into tumors and suppressed tumor growth. 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 a shorter patient survival. Conclusions: 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.

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