title: MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer.
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.
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Catherine
authors: C
authors: Olesch
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Weixiao
authors: W
authors: Sha
authors: Institute of Clinical Pharmacology/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Carlo
authors: C
authors: Angioni
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Lisa Katharina
authors: LK
authors: Sha
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Elias
authors: E
authors: Açaf
authors: Department of Neuroscience, Imaging and Clinical Sciences and Center of Excellence on Aging (CeSI), "G. d'Annunzio" University, Chieti, Italy.
authors: Paola
authors: P
authors: Patrignani
authors: Department of Medicine, Rheumatology Research Unit, Karolinska Institutet, Stockholm, Sweden.
authors: Per-Johan
authors: PJ
authors: Jakobsson
authors: Pharmazentrum Frankfurt/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Heinfried H
authors: HH
authors: Radeke
authors: Institute of Clinical Pharmacology/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Sabine
authors: S
authors: Grösch
authors: Institute of Clinical Pharmacology/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Gerd
authors: G
authors: Geisslinger
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Andreas
authors: A
authors: von Knethen
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Andreas
authors: A
authors: Weigert
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
authors: Bernhard
authors: B
authors: Brüne
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061986:MCF-7 Cells; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D018122:B7-1 Antigen; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: costimulation; cytotoxicity; macrophage polarization; microenvironment; prostaglandins