期刊
ONCOTARGET
卷 6, 期 12, 页码 10284-10296出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3581
关键词
prostaglandins; microenvironment; macrophage polarization; costimulation; cytotoxicity
资金
- Deutsche Forschungsgemeinschaft [SFB 1039]
- Deutsche Krebshilfe [111578, 110637]
- Sander Foundation [2013.036.1]
- Else Kroner-Fresenius-Siftung (Else Kroner-Fresenius-Graduiertenkolleg)
- Else Kroner-Fresenius-Siftung (Translational Research Innovation Pharma, TRIP)
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.
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