title: Melanoma NOS1 expression promotes dysfunctional IFN signaling.
abstract: In multiple forms of cancer, constitutive activation of type I IFN signaling is a critical consequence of immune surveillance against cancer; however, PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Comparison of gene transcription and array comparative genomic hybridization (aCGH) between melanoma cells from different patients indicated that suppression of IFN-α signaling correlates with an amplification of the NOS1 locus within segment 12q22-24. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α. Furthermore, in an explorative study, NOS1 expression in melanoma metastases was negatively associated with patient response to adoptive T cell therapy. This study provides a link between cancer cell phenotype and IFN signal dysfunction in circulating immune cells.
authors.forename: Qiuzhen
authors.initials: Q
authors.lastname: Liu
authors.forename: Sara
authors.initials: S
authors.lastname: Tomei
authors.forename: Maria Libera
authors.initials: ML
authors.lastname: Ascierto
authors.forename: Valeria
authors.initials: V
authors.lastname: De Giorgi
authors.forename: Davide
authors.initials: D
authors.lastname: Bedognetti
authors.forename: Cuilian
authors.initials: C
authors.lastname: Dai
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Uccellini
authors.forename: Tara
authors.initials: T
authors.lastname: Spivey
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Pos
authors.forename: Jaime
authors.initials: J
authors.lastname: Thomas
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reinboth
authors.forename: Daniela
authors.initials: D
authors.lastname: Murtas
authors.forename: Qianbing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lotfi
authors.initials: L
authors.lastname: Chouchane
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Weiss
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
authors.forename: Peter P
authors.initials: PP
authors.lastname: Lee
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Harvey
authors.initials: H
authors.lastname: Alter
authors.forename: Kaitai
authors.initials: K
authors.lastname: Yao
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D019264:Adoptive Transfer; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D055028:Comparative Genomic Hybridization; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction
chemical_list: D016898:Interferon-alpha; D009363:Neoplasm Proteins; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I