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The COX2 Effector Microsomal PGE2 Synthase 1 is a Regulator of Immunosuppression in Cutaneous Melanoma
- Source :
- Clinical Cancer Research. 25:1650-1663
- Publication Year :
- 2019
- Publisher :
- American Association for Cancer Research (AACR), 2019.
-
Abstract
- 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+ 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Skin Neoplasms
medicine.medical_treatment
Programmed Cell Death 1 Receptor
CD8-Positive T-Lymphocytes
Article
Dinoprostone
Immunomodulation
Mice
03 medical and health sciences
Antineoplastic Agents, Immunological
0302 clinical medicine
Immune system
Cell Line, Tumor
medicine
Animals
Humans
Melanoma
Prostaglandin-E Synthases
Tissue microarray
business.industry
Immunosuppression
Immunotherapy
Prognosis
medicine.disease
Gene Expression Regulation, Neoplastic
Disease Models, Animal
030104 developmental biology
Oncology
Cyclooxygenase 2
Cell culture
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Cutaneous melanoma
Cancer research
Cytokines
Tumor Escape
Inflammation Mediators
business
CD8
Signal Transduction
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....b2f4d96b77844773f26d2a5ad747083b