TY  - JOUR
A1  - Olesch, Catherine
A1  - Sha, Weixiao
A1  - Angioni, Carlo Federico
A1  - Sha, Lisa Katharina
A1  - Açaf, Elias
A1  - Patrignani, Paola
A1  - Jakobsson, Per-Johan
A1  - Radeke, Heinfried H.
A1  - Grösch, Sabine
A1  - Geisslinger, Gerd
A1  - Knethen, Andreas von
A1  - Weigert, Andreas
A1  - Brüne, Bernhard
T1  - MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer
T2  - Oncotarget
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.
KW  - prostaglandins
KW  - microenvironment
KW  - macrophage polarization
KW  - costimulation
KW  - cytotoxicity
Y1  - 2015
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/37217
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-372178
UR  - http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=3581
SN  - 1949-2553
N1  - 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.
SP  - 1
EP  - 13
PB  - Impact Journals LLC
CY  - [S.l.]
ER  -