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

// Catherine Olesch 1,* , Weixiao Sha 1,* , Carlo Angioni 2 , Lisa Katharina Sha 1 , Elias Açaf 1 , Paola Patrignani 3 , Per-Johan Jakobsson 4 , Heinfried H. Radeke 5 , Sabine Grösch 2 , Gerd Geisslinger 2 , Andreas von Knethen 1 , Andreas Weigert 1 and Bernhard Brüne 1 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 * These authors contributed equally to the work Correspondence to: Bernhard Brüne, email: // Andreas Weigert, email: // Keywords : prostaglandins, microenvironment, macrophage polarization, costimulation, cytotoxicity Received : July 08, 2014 Accepted : February 13, 2015 Published : March 14, 2015 Abstract Prostaglandin E 2 (PGE 2 ) 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 PGE 2 , 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.