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Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release
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| Veröffentlicht in: | The journal of immunology 188(2012), 11, Seite 5365-5376 |
|---|---|
| Personen und Körperschaften: | , , |
| Titel: | Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release/ 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 |
| Format: | E-Book-Kapitel |
| Sprache: | Englisch |
| veröffentlicht: |
23 April 2012
|
| Gesamtaufnahme: |
: The journal of immunology, 188(2012), 11, Seite 5365-5376
, volume:188 |
| Quelle: | Verbunddaten SWB Lizenzfreie Online-Ressourcen |
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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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| contents | 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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| spelling | Jayaraman, Padmini VerfasserIn (DE-588)1164982613 (DE-627)1029197938 (DE-576)510181252 aut, Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release 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, 23 April 2012, 12, Text txt rdacontent, Computermedien c rdamedia, Online-Ressource cr rdacarrier, Prepublished online 23 April 2012, Gesehen am 20.08.2018, 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., Ramacher, Marcel 1980- VerfasserIn (DE-588)1028857500 (DE-627)731733037 (DE-576)376299967 aut, Umansky, Viktor 1955- VerfasserIn (DE-588)102885756X (DE-627)731733207 (DE-576)376300078 aut, Enthalten in The journal of immunology Bethesda, Md. : Soc., 1916 188(2012), 11, Seite 5365-5376 Online-Ressource (DE-627)269535217 (DE-600)1475085-5 (DE-576)079963838 1550-6606 nnns, volume:188 year:2012 number:11 pages:5365-5376 extent:12, http://www.jimmunol.org/content/188/11/5365 Verlag kostenfrei Volltext, http://dx.doi.org/10.4049/jimmunol.1103553 Verlag Resolving-System kostenfrei Volltext, http://www.jimmunol.org/content/188/11/5365 LFER, LFER 2018-09-13T00:00:00Z |
| spellingShingle | Jayaraman, Padmini, Ramacher, Marcel, Umansky, Viktor, 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 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. |
| swb_id_str | 510181791 |
| title | Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release |
| title_auth | Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release |
| title_full | Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release 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 |
| title_fullStr | Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release 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 |
| title_full_unstemmed | Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release 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 |
| title_in_hierarchy | Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release / 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, |
| title_short | Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release |
| title_sort | tumor expressed inducible nitric oxide synthase controls induction of functional myeloid derived suppressor cells through modulation of vascular endothelial growth factor release |
| url | http://www.jimmunol.org/content/188/11/5365, http://dx.doi.org/10.4049/jimmunol.1103553 |