Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 5, Pages 1650-1663Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-1163
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Funding
- University of Texas MD Anderson Cancer Center SPORE in melanoma [P50CA093459]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- MD Anderson Cancer Center Melanoma Moonshot Program
- Colorectal Cancer Moonshot Program
- Jim Mulva Foundation
- AIM Foundation
- NCI Cancer Center Support Grant [P30CA016672]
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Purpose: Microsomal prostaglandin E2 synthase 1(mPGES1) was evaluated as an important downstream effector of the 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. Pharmacologic inhibitors and syngeneic mouse models using PTGES-knockout (KO) mouse melanoma cell lines were used to evaluate the mPGES1-mediated immunosuppressive function. Results: 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, PTGES KO increased melanoma expression of PD-L1, increased infiltration of CD8a(+) T cells, and CD8a thorn dendritic cells into tumors and suppressed tumor growth. Durable tumor regression was observed in mice bearing PTGES 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. 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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