IRF-1 responsiveness to IFN-γ predicts different cancer immune phenotypes

• Published in: British journal of cancer Vol. 109; no. 1; pp. 76 - 82
• Main Authors: Murtas, D, Maric, D, De Giorgi, V, Reinboth, J, Worschech, A, Fetsch, P, Filie, A, Ascierto, M L, Bedognetti, D, Liu, Q, Uccellini, L, Chouchane, L, Wang, E, Marincola, F M, Tomei, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.07.2013; Nature Publishing Group
• Subjects: 631/250/127/1212; 631/67/1059/2325; beta Catenin - metabolism; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Chromosome aberrations; Drug Resistance; Enzyme Activation; Epidemiology; Humans; Immunotherapy; Interferon Regulatory Factor-1 - metabolism; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Medical genetics; Medical sciences; Melanoma - immunology; Melanoma - therapy; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); NF-kappa B - metabolism; Oncology; TOR Serine-Threonine Kinases - metabolism; Transcription, Genetic; Translational Therapeutics; Tumor Necrosis Factor-alpha - pharmacology; Tumors; Wnt Proteins - metabolism; IFN; B; nuclear translocation; NF; IRF-1; immune phenotype; TNF; Chromosomal aberration; Cytokine; Prediction; Interferon regulatory factor 1; Malignant tumor; NF-κB; Phenotype; IFN-γ; Cancerology; TNF-α; Cytogenetics; Abnormal chromosome; Transcription factor NFκB; Predictive factor; Tumor necrosis factor α; Cancer; Gamma interferon; Chromosome translocation
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.335

Background: Several lines of evidence suggest a dichotomy between immune active and quiescent cancers, with the former associated with a good prognostic phenotype and better responsiveness to immunotherapy. Central to such dichotomy is the master regulator of the acute inflammatory process interferon regulatory factor (IRF)-1. However, it remains unknown whether the responsiveness of IRF-1 to cytokines is able to differentiate cancer immune phenotypes. Methods: IRF-1 activation was measured in 15 melanoma cell lines at basal level and after treatment with IFN- γ , TNF- α and a combination of both. Microarray analysis was used to compare transcriptional patterns between cell lines characterised by high or low IRF-1 activation. Results: We observed a strong positive correlation between IRF-1 activation at basal level and after IFN- γ and TNF- α treatment. Microarray demonstrated that three cell lines with low and three with high IRF-1 inducible translocation scores differed in the expression of 597 transcripts. Functional interpretation analysis showed mTOR and Wnt/ β -cathenin as the top downregulated pathways in the cell lines with low inducible IRF-1 activation, suggesting that a low IRF-1 inducibility recapitulates a cancer phenotype already described in literature characterised by poor prognosis. Conclusion: Our findings support the central role of IRF-1 in influencing different tumour phenotypes.