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

• Published in: Clinical cancer research 2019-03, Vol.25 (5), p.1650-1663
• Main Authors: Kim, Sun-Hee, Roszik, Jason, Cho, Sung-Nam, Ogata, Dai, Milton, Denái R, Peng, Weiyi, Menter, David G, Ekmekcioglu, Suhendan, Grimm, Elizabeth A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Immunological - pharmacology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cyclooxygenase 2 - metabolism; Cytokines - metabolism; Dinoprostone - metabolism; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Immunomodulation - genetics; Inflammation Mediators; Melanoma - drug therapy; Melanoma - etiology; Melanoma - metabolism; Melanoma - pathology; Melanoma, Cutaneous Malignant; Mice; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Prostaglandin-E Synthases - genetics; Prostaglandin-E Synthases - metabolism; Signal Transduction; Skin Neoplasms - drug therapy; Skin Neoplasms - etiology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tumor Escape - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-1163

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 ( = 91) was performed to assess the association between mPGES1, COX2, CD8, and patient survival. Pharmacologic inhibitors and syngeneic mouse models using -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, 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 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.