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Oncotarget. 2015 Apr 30;6(12):10284-96.

MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer.

Author information

1
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
2
Institute of Clinical Pharmacology/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
3
Department of Neuroscience, Imaging and Clinical Sciences and Center of Excellence on Aging (CeSI), "G. d'Annunzio" University, Chieti, Italy.
4
Department of Medicine, Rheumatology Research Unit, Karolinska Institutet, Stockholm, Sweden.
5
Pharmazentrum Frankfurt/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.

Abstract

Prostaglandin E2 (PGE2) favors multiple aspects of tumor development and immune evasion. Therefore, microsomal prostaglandin E synthase (mPGES-1/-2), is a potential target for cancer therapy. We explored whether inhibiting mPGES-1 in human and mouse models of breast cancer affects tumor-associated immunity. A new model of breast tumor spheroid killing by human PBMCs was developed. In this model, tumor killing required CD80 expression by tumor-associated phagocytes to trigger cytotoxic T cell activation. Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression. Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice. Macrophages of mPGES-1(-/-) PyMT mice indeed expressed elevated levels of CD80 compared to their wildtype counterparts. CD80 expression in tumor-spheroid infiltrating mPGES-1(-/-) macrophages translated into antigen-specific cytotoxic T cell activation. In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth. We propose that mPGES-1 inhibition in combination with immune cell activation might be part of a therapeutic strategy to overcome the immunosuppressive tumor microenvironment.

KEYWORDS:

costimulation; cytotoxicity; macrophage polarization; microenvironment; prostaglandins

PMID:
25871398
PMCID:
PMC4496355
DOI:
10.18632/oncotarget.3581
[Indexed for MEDLINE]
Free PMC Article

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