title: Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release.
abstract: 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.
authors.affiliation: Department of Otolaryngology, Mount Sinai School of Medicine, New York, NY 10028, USA.
authors.forename: Padmini
authors.initials: P
authors.lastname: Jayaraman
authors.forename: Falguni
authors.initials: F
authors.lastname: Parikh
authors.forename: Esther
authors.initials: E
authors.lastname: Lopez-Rivera
authors.forename: Yared
authors.initials: Y
authors.lastname: Hailemichael
authors.forename: Amelia
authors.initials: A
authors.lastname: Clark
authors.forename: Ge
authors.initials: G
authors.lastname: Ma
authors.forename: David
authors.initials: D
authors.lastname: Cannan
authors.forename: Marcel
authors.initials: M
authors.lastname: Ramacher
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.forename: Shu-Hsia
authors.initials: SH
authors.lastname: Chen
authors.forename: Viktor Y
authors.initials: VY
authors.lastname: Umansky
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D007108:Immune Tolerance / Q000235:genetics; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*
chemical_list: D042442:Vascular Endothelial Growth Factors; D052247:Nitric Oxide Synthase Type II