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Interferon-γ links ultraviolet radiation to melanomagenesis in mice


Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood1,2. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA3,4. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients.

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Figure 1: Melanocyte-specific GFP expression reveals UVB-induced activation.
Figure 2: UVB-induced melanocyte activation is mediated by IFN-γ.
Figure 3: UVB induces chemoattraction of IFN-γ-producing macrophages into neonatal skin.
Figure 4: IFN-γ mediates pro-tumorigenic effects of UVB-recruited skin macrophages.

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Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the Gene Expression Omnibus (GEO) database ( under accessionnumber GSE25164.


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We would like to thank the following individuals for their support: S. Yuspa for primary keratinocytes; C. Toniatti and H. Bujard for the rtTA2sM2 construct; V. Hearing for melan-c cell line; S. Hewitt for the human melanoma tissue microarray; M. Anver for immunohistochemical staining and production/analysis of mouse melanoma tissue microarray; K. Blas and E. Vega-Valle for technical help; N. Restifo and A. Hurwitz for suggestions and discussions. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. M.R.Z. was supported by a National Cancer Institute Director’s Innovation Career Development Award. E.C.D. and F.P.N. were supported by grants from the National Institutes of Health (awards CA53765 and CA92258), and the Melanoma Research Foundation.

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Authors and Affiliations



M.R.Z. designed and performed experiments, interpreted data and wrote the manuscript. S.D. performed statistical analysis of microarray data and generated heatmaps. F.P.N. interpreted data and reviewed the manuscript. C.G.-C. managed mouse colonies. T.S.H. performed flow cytometry and FACS. R.L.W. performed cDNA microarrays. L.F. produced Dct-rtTA transgenic mice. E.F. provided TRE-H2B–GFP mice. L.L. helped design interferon blockade experiments. H.A.Y. interpreted data and reviewed the manuscript. T.J.H. evaluated GFP expression in skin and reviewed the manuscript. H.A. evaluated embryonic expression of GFP and reviewed the manuscript. G.T. designed interferon blockade experiments, provided antibodies, and reviewed the manuscript. P.S.M. designed and performed analysis of microarray data and reviewed manuscript. E.C.D. designed, measured and performed UV irradiation experiments, supervised project, and reviewed manuscript. G.M. designed experiments, interpreted data, supervised the project and wrote the manuscript.

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Correspondence to Edward C. De Fabo or Glenn Merlino.

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Zaidi, M., Davis, S., Noonan, F. et al. Interferon-γ links ultraviolet radiation to melanomagenesis in mice. Nature 469, 548–553 (2011).

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