Melanoma NOS1 expression promotes dysfunctional IFN signaling
Qiuzhen Liu, … , Ena Wang, Francesco M. Marincola
Qiuzhen Liu, … , Ena Wang, Francesco M. Marincola
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):2147-2159. https://doi.org/10.1172/JCI69611.
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Research Article Oncology

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

Qiuzhen Liu, Sara Tomei, Maria Libera Ascierto, Valeria De Giorgi, Davide Bedognetti, Cuilian Dai, Lorenzo Uccellini, Tara Spivey, Zoltan Pos, Jaime Thomas, Jennifer Reinboth, Daniela Murtas, Qianbing Zhang, Lotfi Chouchane, Geoffrey R. Weiss, Craig L. Slingluff Jr., Peter P. Lee, Steven A. Rosenberg, Harvey Alter, Kaitai Yao, Ena Wang, Francesco M. Marincola

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Figure 5

12q22-24 amplification is a genomic marker for L-mel and targets the NOS1 gene.

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12q22-24 amplification is a genomic marker for L-mel and targets the NOS...
(A) Top: Chromosomal amplifications (red) and deletions (blue) in L-mels (above) and H-mels (below). Differences between L-mels and H-mels focused on chr8 and chr12 (blue squares). Bottom panel: Ten segments (red triangles) identified by ANOVA comparing L-mels with H-mels (cutoff of P < 0.01, fold change of less than –2 or greater than 2). The segments are located in chr8, chr10, and chr12 (4, 1, and 5 segments, respectively). (B) Top: Copy number values in chr12q22-24 including the most significant segment and 2 other flanking segments in which the NOS1 gene is located (cutoff of P < 0.00001). Bottom: Venn diagram assembling 168 genes from 3 overlapping segments in chr12q22-24 with the 6,771 differentially expressed genes between L-mels and H-mels; 19 were in common between the two platforms, and their symbols are displayed. (C) Left: NOS1 mRNA values in L-mels (blue) were higher than those in H-mels (red) (P = 0.001, Mann-Whitney U test). Right: NOS1 protein and RNA correlation in 8 melanoma lines tested by intracellular FACS analysis. (D) Left: Correlation between NOS1 mRNA values in melanoma cells (x axis) and IFN-α-p-STAT1 levels (y axis) in corresponding cocultured CD4+ and CD8+ T cells and monocytes. Right: Correlation between NOS1 mRNA values in melanoma cells (x axis) and their IFN-α-p-STAT1 levels (y axis). All correlation analyses in this figure are based on Spearman’s correlation test.