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MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer.
Oncotarget. 2015 Apr 30; 6(12):10284-96.O

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+Show Affiliations

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

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25871398

Citation

Olesch, Catherine, et al. "MPGES-1-derived PGE2 Suppresses CD80 Expression On Tumor-associated Phagocytes to Inhibit Anti-tumor Immune Responses in Breast Cancer." Oncotarget, vol. 6, no. 12, 2015, pp. 10284-96.
Olesch C, Sha W, Angioni C, et al. MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer. Oncotarget. 2015;6(12):10284-96.
Olesch, C., Sha, W., Angioni, C., Sha, L. K., Açaf, E., Patrignani, P., Jakobsson, P. J., Radeke, H. H., Grösch, S., Geisslinger, G., von Knethen, A., Weigert, A., & Brüne, B. (2015). MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer. Oncotarget, 6(12), 10284-96.
Olesch C, et al. MPGES-1-derived PGE2 Suppresses CD80 Expression On Tumor-associated Phagocytes to Inhibit Anti-tumor Immune Responses in Breast Cancer. Oncotarget. 2015 Apr 30;6(12):10284-96. PubMed PMID: 25871398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer. AU - Olesch,Catherine, AU - Sha,Weixiao, AU - Angioni,Carlo, AU - Sha,Lisa Katharina, AU - Açaf,Elias, AU - Patrignani,Paola, AU - Jakobsson,Per-Johan, AU - Radeke,Heinfried H, AU - Grösch,Sabine, AU - Geisslinger,Gerd, AU - von Knethen,Andreas, AU - Weigert,Andreas, AU - Brüne,Bernhard, PY - 2014/07/08/received PY - 2015/02/13/accepted PY - 2015/4/15/entrez PY - 2015/4/15/pubmed PY - 2016/3/16/medline KW - costimulation KW - cytotoxicity KW - macrophage polarization KW - microenvironment KW - prostaglandins SP - 10284 EP - 96 JF - Oncotarget JO - Oncotarget VL - 6 IS - 12 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/25871398/MPGES_1_derived_PGE2_suppresses_CD80_expression_on_tumor_associated_phagocytes_to_inhibit_anti_tumor_immune_responses_in_breast_cancer_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=3581 DB - PRIME DP - Unbound Medicine ER -