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.

Combining type I Interferons and 5-aza-2'-deoxycitidine to improve anti-tumor response against melanoma / Lucarini, V; Buccione, C; Ziccheddu, G; Peschiaroli, F; Sestili, P; Puglisi, R; Mattia, G; Zanetti, C; Parolini, I; Bracci, L; Macchia, I; Rossi, A; D'Urso, Mt; Macchia, D; Spada, M; De Ninno, A; Gerardino, A; Mozetic, P; Trombetta, M; Rainer, A; Businaro, L; Schiavoni, G; Mattei, F. - In: JOURNAL OF INVESTIGATIVE DERMATOLOGY. - ISSN 0022-202X. - 137:1(2017), pp. 159-169. [10.1016/j.jid.2016.08.024]

Combining type I Interferons and 5-aza-2'-deoxycitidine to improve anti-tumor response against melanoma

Lucarini V;Rossi A;
2017

Abstract

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.
2017
decitabine; melanoma; type I interferon
01 Pubblicazione su rivista::01a Articolo in rivista
Combining type I Interferons and 5-aza-2'-deoxycitidine to improve anti-tumor response against melanoma / Lucarini, V; Buccione, C; Ziccheddu, G; Peschiaroli, F; Sestili, P; Puglisi, R; Mattia, G; Zanetti, C; Parolini, I; Bracci, L; Macchia, I; Rossi, A; D'Urso, Mt; Macchia, D; Spada, M; De Ninno, A; Gerardino, A; Mozetic, P; Trombetta, M; Rainer, A; Businaro, L; Schiavoni, G; Mattei, F. - In: JOURNAL OF INVESTIGATIVE DERMATOLOGY. - ISSN 0022-202X. - 137:1(2017), pp. 159-169. [10.1016/j.jid.2016.08.024]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1405976
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