Oncotarget

Research Papers:

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

Catherine Olesch, Weixiao Sha, Carlo Angioni, Lisa Katharina Sha, Elias Açaf, Paola Patrignani, Per-Johan Jakobsson, Heinfried H. Radeke, Sabine Grösch, Gerd Geisslinger, Andreas von Knethen, Andreas Weigert and Bernhard Brüne _

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Oncotarget. 2015; 6:10284-10296. https://doi.org/10.18632/oncotarget.3581

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Abstract

Catherine Olesch1,*, Weixiao Sha1,*, Carlo Angioni2, Lisa Katharina Sha1, Elias Açaf1, Paola Patrignani3, Per-Johan Jakobsson4, Heinfried H. Radeke5, Sabine Grösch2, Gerd Geisslinger2, Andreas von Knethen1, Andreas Weigert1 and Bernhard Brüne1

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 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.


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