Melanoma NOS1 expression promotes dysfunctional IFN signaling

Liu, Q;Tomei, S;Ascierto, ML;De Giorgi, V;Bedognetti, D;Dai, C;Uccellini, L;Spivey, T;Pos, Z;Thomas, J;Reinboth, J;MURTAS, DANIELA;Zhang, Q;Chouchane, L;Weiss, GR;Slingluff, CL J.r.;Lee, PP;Rosenberg, SA;Alter, H;Yao, K;Wang, E;Marincola, FM

2014-01-01

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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.