title: Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways.
abstract: The accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is a hallmark of malignancy-associated inflammation and a major mediator for the induction of T cell suppression in cancer. MDSC can be divided phenotypically into granulocytic (G-MDSC) and monocytic (Mo-MDSC) subgroups. Several mechanisms mediate the induction of T cell anergy by MDSC; however, the specific role of these pathways in the inhibitory activity of MDSC subpopulations remains unclear. Therefore, we aimed to determine the effector mechanisms by which subsets of tumor-infiltrating MDSC block T cell function. We found that G-MDSC had a higher ability to impair proliferation and expression of effector molecules in activated T cells, as compared to Mo-MDSC. Interestingly, both MDSC subgroups inhibited T cells through nitric oxide (NO)-related pathways, but expressed different effector inhibitory mechanisms. Specifically, G-MDSC impaired T cells through the production of peroxynitrites (PNT), while Mo-MDSC suppressed by the release of NO. The production of PNT in G-MDSC depended on the expression of gp91(phox) and endothelial NO synthase (eNOS), while inducible NO synthase (iNOS) mediated the generation of NO in Mo-MDSC. Deletion of eNOS and gp91(phox) or scavenging of PNT blocked the suppressive function of G-MDSC and induced anti-tumoral effects, without altering Mo-MDSC inhibitory activity. Furthermore, NO-scavenging or iNOS knockdown prevented Mo-MDSC function, but did not affect PNT production or suppression by G-MDSC. These results suggest that MDSC subpopulations utilize independent effector mechanisms to regulate T cell function. Inhibition of these pathways is expected to specifically block MDSC subsets and overcome immune suppression in cancer.
authors.affiliation: Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA; Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Raber
authors.forename: Paul
authors.initials: P
authors.lastname: Thevenot
authors.forename: Rosa
authors.initials: R
authors.lastname: Sierra
authors.forename: Dorota
authors.initials: D
authors.lastname: Wyczechowska
authors.forename: Daniel
authors.initials: D
authors.lastname: Halle
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ramirez
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Ochoa
authors.forename: Matthew
authors.initials: M
authors.lastname: Fletcher
authors.forename: Cruz
authors.initials: C
authors.lastname: Velasco
authors.forename: Anna
authors.initials: A
authors.lastname: Wilk
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006098:Granulocytes / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D009369:Neoplasms / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D009573:Nitrites / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000096:biosynthesis / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D008562:Membrane Glycoproteins; D009573:Nitrites; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: MDSC; eNOS; peroxynitrites