Catherine Olesch, Weixiao Sha, Carlo Federico Angioni, Lisa Sha, Elias Açaf, Paola Patrignani, Per-Johan Jakobsson, Heinfried H. Radeke, Sabine Grösch, Gerd Geisslinger, Andreas von Knethen, Andreas Weigert, Bernhard Brüne
- 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.
MetadatenAuthor: | Catherine OleschORCiDGND, Weixiao Sha, Carlo Federico AngioniORCiD, Lisa ShaGND, Elias Açaf, Paola PatrignaniORCiD, Per-Johan Jakobsson, Heinfried H. RadekeORCiDGND, Sabine GröschORCiDGND, Gerd GeisslingerORCiDGND, Andreas von KnethenORCiDGND, Andreas WeigertORCiDGND, Bernhard BrüneORCiD |
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URN: | urn:nbn:de:hebis:30:3-372178 |
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URL: | http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=3581 |
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DOI: | https://doi.org/10.18632/oncotarget.3581 |
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ISSN: | 1949-2553 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/25871398 |
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Parent Title (English): | Oncotarget |
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Publisher: | Impact Journals LLC |
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Place of publication: | [S.l.] |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2015/03/14 |
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Date of first Publication: | 2015/03/14 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2015/04/20 |
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Tag: | costimulation; cytotoxicity; macrophage polarization; microenvironment; prostaglandins |
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Page Number: | 13 |
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First Page: | 1 |
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Last Page: | 13 |
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Note: | This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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HeBIS-PPN: | 36898060X |
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Institutes: | Biochemie, Chemie und Pharmazie / Biochemie und Chemie |
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| Medizin / Medizin |
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| Fachübergreifende Einrichtungen / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES) |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 3.0 |
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