Combining Type I Interferons and 5-Aza-2′-Deoxycitidine to Improve Anti-Tumor Response against Melanoma

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• 作者：Valeria Lucarini¹ ; ⁵ ; Carla Buccione¹ ; ⁵ ; Giovanna Ziccheddu¹ ; Francesca Peschiaroli¹ ; Paola Sestili¹ ; Rossella Puglisi¹ ; Gianfranco Mattia¹ ; Cristiana Zanetti¹ ; Isabella Parolini¹ ; Laura Bracci¹ ; Iole Macchia¹ ; Alessandra Rossi¹ ; Maria Teresa D'Urso¹ ; Daniele Macchia¹ ; Massimo Spada¹ ; Adele De Ninno² ; Annamaria Gerardino² ; Pamela Mozetic⁴ ; Marcella Trombetta⁴ ; Alberto Rainer⁴ ; Luca Businaro² ; ³ ; Giovanna Schiavoni¹ ; ⁶ ; Fabrizio Mattei¹ ; ⁶ ; ^{fabrizio.mattei@iss.it}
• 关键词：DAC ; decitabine ; ISG ; interferon-stimulated gene ; MDSC ; myeloid-derived suppressor cell ; MTS ; 3-(4 ; 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium ; OVA ; ovalbumin ; PBMC ; peripheral blood mononuclear cell ; Treg ; regulatory T cell
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：137
• 期：1
• 页码：159-169
• 全文大小：3934 K
• 卷排序：137

文摘

Resistance to IFN-I–induced antineoplastic effects has been reported in many tumors and arises, in part, from epigenetic silencing of IFN-stimulated genes by DNA methylation. We hypothesized that restoration of IFN-stimulated genes by co-administration of the demethylating drug 5-aza-2′-deoxycitidine (decitabine [DAC]) may enhance the susceptibility to IFN-I–mediated antitumoral effects in melanoma. We show that combined administration of IFN-I and DAC significantly inhibits the growth of murine and human melanoma cells, both in vitro and in vivo. Compared with controls, DAC/IFN-I–treated melanoma cells exhibited reduced cell growth, augmented apoptosis, and diminished migration. Moreover, IFN-I and DAC synergized to suppress the growth of three-dimensional human melanoma spheroids, altering tumor architecture. These direct antitumor effects correlated with induction of the IFN-stimulated gene Mx1. In vivo, DAC/IFN-I significantly reduced melanoma growth via stimulation of adaptive immunity, promoting tumor-infiltrating CD8+ T cells while inhibiting the homing of immunosuppressive CD11b+ myeloid cells and regulatory T cells. Accordingly, exposure of human melanoma cells to DAC/IFN-I induced the recruitment of immune cells toward the tumor in a Matrigel (Corning Life Sciences, Kennebunkport, ME)-based microfluidic device. Our findings underscore a beneficial effect of DAC plus IFN-I combined treatment against melanoma through both direct and immune-mediated anti-tumor effects.