Melanoma NOS1 expression promotes dysfunctional IFN signaling

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, Peter P. Lee, Steven A. Rosenberg, Harvey Alter, Kaitai YaoEna Wang, Francesco M. Marincola

Research output: Contribution to journalArticle

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-αresponse 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-αsignaling 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.

Original languageEnglish (US)
Pages (from-to)2147-2159
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number5
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Medicine(all)

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    Liu, Q., Tomei, S., Ascierto, M. L., De Giorgi, V., Bedognetti, D., Dai, C., Uccellini, L., Spivey, T., Pos, Z., Thomas, J., Reinboth, J., Murtas, D., Zhang, Q., Chouchane, L., Weiss, G. R., Slingluff, C. L., Lee, P. P., Rosenberg, S. A., Alter, H., ... Marincola, F. M. (2014). Melanoma NOS1 expression promotes dysfunctional IFN signaling. Journal of Clinical Investigation, 124(5), 2147-2159. https://doi.org/10.1172/JCI69611