Melanoma NOS1 expression promotes dysfunctional IFN signaling.
J Clin Invest
; 124(5): 2147-59, 2014 May.
Article
in En
| MEDLINE
| ID: mdl-24691438
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Gene Expression Regulation, Enzymologic
/
Gene Expression Regulation, Neoplastic
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Interferon-alpha
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Nitric Oxide Synthase Type I
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Melanoma
/
Neoplasm Proteins
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
J Clin Invest
Year:
2014
Document type:
Article