Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release
Inducible NO synthase (iNOS) is a hallmark of chronic inflammation that is also overexpressed in melanoma and other cancers. Whereas iNOS is a known effector of myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, its pivotal position at the interface of inflammation and cancer also ma...
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| Hauptverfasser: | , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
23 April 2012
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| In: |
The journal of immunology
Year: 2012, Jahrgang: 188, Heft: 11, Pages: 5365-5376 |
| ISSN: | 1550-6606 |
| DOI: | 10.4049/jimmunol.1103553 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://www.jimmunol.org/content/188/11/5365 Verlag, kostenfrei, Volltext: http://dx.doi.org/10.4049/jimmunol.1103553 
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| Verfasserangaben: | Padmini Jayaraman, Falguni Parikh, Esther Lopez-Rivera, Yared Hailemichael, Amelia Clark, Ge Ma, David Cannan, Marcel Ramacher, Masashi Kato, Willem W. Overwijk, Shu-Hsia Chen, Viktor Y. Umansky, Andrew G. Sikora |
MARC
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| 245 | 1 | 0 | |a Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release |c Padmini Jayaraman, Falguni Parikh, Esther Lopez-Rivera, Yared Hailemichael, Amelia Clark, Ge Ma, David Cannan, Marcel Ramacher, Masashi Kato, Willem W. Overwijk, Shu-Hsia Chen, Viktor Y. Umansky, Andrew G. Sikora |
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| 520 | |a Inducible NO synthase (iNOS) is a hallmark of chronic inflammation that is also overexpressed in melanoma and other cancers. Whereas iNOS is a known effector of myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, its pivotal position at the interface of inflammation and cancer also makes it an attractive candidate regulator of MDSC recruitment. We hypothesized that tumor-expressed iNOS controls MDSC accumulation and acquisition of suppressive activity in melanoma. CD11b+GR1+ MDSC derived from mouse bone marrow cells cultured in the presence of MT-RET-1 mouse melanoma cells or conditioned supernatants expressed STAT3 and reactive oxygen species (ROS) and efficiently suppressed T cell proliferation. Inhibition of tumor-expressed iNOS with the small molecule inhibitor L-NIL blocked accumulation of STAT3/ROS-expressing MDSC, and abolished their suppressive function. Experiments with vascular endothelial growth factor (VEGF)-depleting Ab and recombinant VEGF identified a key role for VEGF in the iNOS-dependent induction of MDSC. These findings were further validated in mice bearing transplantable MT-RET-1 melanoma, in which L-NIL normalized elevated serum VEGF levels; downregulated activated STAT3 and ROS production in MDSC; and reversed tumor-mediated immunosuppression. These beneficial effects were not observed in iNOS knockout mice, suggesting L-NIL acts primarily on tumor- rather than host-expressed iNOS to regulate MDSC function. A significant decrease in tumor growth and a trend toward increased tumor-infiltrating CD8+ T cells were also observed in MT-RET transgenic mice bearing spontaneous tumors. These data suggest a critical role for tumor-expressed iNOS in the recruitment and induction of functional MDSC by modulation of tumor VEGF secretion and upregulation of STAT3 and ROS in MDSC. | ||
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