title: IRF-8 controls melanoma progression by regulating the cross talk between cancer and immune cells within the tumor microenvironment.
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.
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. fabrizio.mattei@iss.it
authors: Fabrizio
authors: F
authors: Mattei
authors: Giovanna
authors: G
authors: Schiavoni
authors: Paola
authors: P
authors: Sestili
authors: Francesca
authors: F
authors: Spadaro
authors: Alessandra
authors: A
authors: Fragale
authors: Antonella
authors: A
authors: Sistigu
authors: Valeria
authors: V
authors: Lucarini
authors: Massimo
authors: M
authors: Spada
authors: Massimo
authors: M
authors: Sanchez
authors: Stefania
authors: S
authors: Scala
authors: Angela
authors: A
authors: Battistini
authors: Filippo
authors: F
authors: Belardelli
authors: Lucia
authors: L
authors: Gabriele
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D018925:Chemokines / Q000378:metabolism*; D000077209:Decitabine; D003713:Dendritic Cells / Q000276:immunology; D018450:Disease Progression; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020239:Receptor Cross-Talk / Q000276:immunology*; D019707:Receptors, Chemokine / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D001374:Azacitidine; D018925:Chemokines; D000077209:Decitabine; D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D007378:Interleukins; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099185:Interferon Regulatory Factor-8