IRF-8 controls melanoma progression by regulating the cross talk between cancer and immune cells within the tumor microenvironment

Fabrizio Mattei, Giovanna Schiavoni, Paola Sestili, Francesca Spadaro, Alessandra Fragale, Antonella Sistigu, Valeria Lucarini, Massimo Spada, Massimo Sanchez, Stefania Scala, Angela Battistini, Filippo Belardelli, Lucia Gabriele

Research output: Contribution to journalArticle

Abstract

The transcription factor interferon regulatory factor-8 (IRF-8) is crucial for myeloid cell development and immune response and also acts as a tumor suppressor gene. Here, we analyzed the role of IRF-8 in the cross talk between melanoma cells and tumor-infiltrating leukocytes. B16-F10 melanoma cells transplanted into IRF-8-deficient (IRF-8-/-) mice grow more rapidly, leading to higher numbers of lung metastasis, with respect to control animals. These events correlated with reduced dendritic cell and T cell infiltration, accumulation of myeloid-derived suppressor cells and a chemokine/chemokine receptor expression profile within the tumor microenvironment supporting tumor growth, angiogenesis, and metastasis. Noticeably, primary tumors developing in IRF-8-/- mice displayed a clear-cut inhibition of IRF-8 expression in melanoma cells. Injection of the demethylating agent 5-aza-2′-deoxycytidine into melanoma bearing IRF-8-/- animals induced intratumoral IRF-8 expression and resulted in the re-establishment of a chemokine/ chemokine receptor pattern favoring leukocyte infiltration and melanoma growth arrest. Importantly, intrinsic IRF-8 - expression was progressively down-modulated during melanoma growth in mice and in human metastatic melanoma cells with respect to primary tumors. Lastly, IRF-8 expression in melanoma cells was directly modulated by soluble factors, among which interleukin-27 (IL-27), released by immune cells from tumor-bearing mice. Collectively, these results underscore a key role of IRF-8 in the cross talk between melanoma and immune cells, thus revealing its critical function within the tumor microenvironment in regulating melanoma progression and invasiveness.

Original languageEnglish
Pages (from-to)1223-1235
Number of pages13
JournalNeoplasia (United States)
Volume14
Issue number12
DOIs
Publication statusPublished - Dec 2012

ASJC Scopus subject areas

  • Cancer Research

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    Mattei, F., Schiavoni, G., Sestili, P., Spadaro, F., Fragale, A., Sistigu, A., Lucarini, V., Spada, M., Sanchez, M., Scala, S., Battistini, A., Belardelli, F., & Gabriele, L. (2012). IRF-8 controls melanoma progression by regulating the cross talk between cancer and immune cells within the tumor microenvironment. Neoplasia (United States), 14(12), 1223-1235. https://doi.org/10.1593/neo.121444