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.
View: Text | PDF
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

×

Figure 7

NOS1 expression by melanoma metastases.

Options: View larger image (or click on image) Download as PowerPoint
NOS1 expression by melanoma metastases. (A) mRNA levels of IFN-α–related...
(A) mRNA levels of IFN-α–related signaling genes in 9 melanoma metastases (left) and simultaneously collected autologous PBMCs (middle) presented as fold change compared with healthy donors’ PBMCs. Right: Scatter plot displaying correlative values for transcripts shown in the previous two panels comparing melanoma metastases (y axis) and PBMCs (x axis); n = 63. (B) Scatter plots correlating ex vivo IFN-α-p-STAT1 (left), IFN-α-p-STAT3/p-STAT1 (middle), and IFN-α-pIRF7 (right) with NOS1 expression in 8 available PBMCs (y axis). (C) Left: lack of normal distribution of NOS1 expression in melanoma metastases (P < 0.01, Kolmogorov-Smirnov normality test) and ranking of the 113 cases into high- and low-expression groups according to the mean NOS1 expression value (4.40). Right: NOS1 expression in melanoma was inversely correlated with therapeutic outcome (Spearman’s rank correlation coefficient). The high-expression NOS1 group was significantly enriched with NR cases (P = 0.011, χ2 test); (D) Left: NOS1 expression in 113 melanoma metastases from patients receiving adoptive TIL therapy segregated according to response to therapy (CR, PR, and NR; P values refer to one-way ANOVA). Right: NOS1 expression in overall response (CR + PR) compared with NR cases (unpaired Student’s t test). (E) Hierarchical clustering of the 113 metastases according to NOS1, NOS2, and NOS3 displaying three groups, one with concordantly high expression of the 3 NOS genes and enriched in NRs, the other with low expression, and the third with discordant expression. All correlative analyses are based on Pearson’s correlation test.