Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Interferon-γ links ultraviolet radiation to melanomagenesis in mice

Abstract

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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accessionnumber GSE25164.

References

  1. Garibyan, L. & Fisher, D. E. How sunlight causes melanoma. Curr. Oncol. Rep. 12, 319–326 (2010)

    CAS  Article  Google Scholar 

  2. Whiteman, D. C., Whiteman, C. A. & Green, A. C. Childhood sun exposure as a risk factor for melanoma: a systematic review of epidemiologic studies. Cancer Causes Control 12, 69–82 (2001)

    CAS  Article  Google Scholar 

  3. Noonan, F. P. et al. Neonatal sunburn and melanoma in mice. Nature 413, 271–272 (2001)

    ADS  CAS  Article  Google Scholar 

  4. De Fabo, E. C., Noonan, F. P., Fears, T. & Merlino, G. Ultraviolet B but not ultraviolet A radiation initiates melanoma. Cancer Res. 64, 6372–6376 (2004)

    CAS  Article  Google Scholar 

  5. Nishimura, E. K. et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature 416, 854–860 (2002)

    ADS  CAS  Article  Google Scholar 

  6. Walker, G. J. et al. Murine neonatal melanocytes exhibit a heightened proliferative response to ultraviolet radiation and migrate to the epidermal basal layer. J. Invest. Dermatol. 129, 184–193 (2009)

    CAS  Article  Google Scholar 

  7. Schroder, K., Hertzog, P. J., Ravasi, T. & Hume, D. A. Interferon-γ: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75, 163–189 (2004)

    CAS  Article  Google Scholar 

  8. Wolnicka-Glubisz, A. et al. Deficient inflammatory response to UV radiation in neonatal mice. J. Leukoc. Biol. 81, 1352–1361 (2007)

    CAS  Article  Google Scholar 

  9. Darwich, L. et al. Secretion of interferon-γ by human macrophages demonstrated at the single-cell level after costimulation with interleukin (IL)-12 plus IL-18. Immunology 126, 386–393 (2009)

    CAS  Article  Google Scholar 

  10. Li, D. et al. Rays and arrays: the transcriptional program in the response of human epidermal keratinocytes to UVB illumination. FASEB J. 15, 2533–2535 (2001)

    CAS  Article  Google Scholar 

  11. Proost, P., Wuyts, A. & Van Damme, J. Human monocyte chemotactic proteins-2 and -3: structural and functional comparison with MCP-1. J. Leukoc. Biol. 59, 67–74 (1996)

    CAS  Article  Google Scholar 

  12. DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009)

    CAS  Article  Google Scholar 

  13. Dunn, G. P., Koebel, C. M. & Schreiber, R. D. Interferons, immunity and cancer immunoediting. Nature Rev. Immunol. 6, 836–848 (2006)

    CAS  Article  Google Scholar 

  14. He, Y. F. et al. Sustained low-level expression of interferon-γ promotes tumor development: potential insights in tumor prevention and tumor immunotherapy. Cancer Immunol. Immunother. 54, 891–897 (2005)

    CAS  Article  Google Scholar 

  15. Aoki, H. & Moro, O. Upregulation of the IFN-γ-stimulated genes in the development of delayed pigmented spots on the dorsal skin of F1 mice of HR-1 x HR/De. J. Invest. Dermatol. 124, 1053–1061 (2005)

    CAS  Article  Google Scholar 

  16. Hirobe, T. Histochemical survey of the distribution of the epidermal melanoblasts and melanocytes in the mouse during fetal and postnatal periods. Anat. Rec. 208, 589–594 (1984)

    CAS  Article  Google Scholar 

  17. Wolnicka-Glubisz, A. & Noonan, F. P. Neonatal susceptibility to UV induced cutaneous malignant melanoma in a mouse model. Photochem. Photobiol. Sci. 5, 254–260 (2006)

    CAS  Article  Google Scholar 

  18. Iliopoulos, D., Jaeger, S. A., Hirsch, H. A., Bulyk, M. L. & Struhl, K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol. Cell 39, 493–506 (2010)

    CAS  Article  Google Scholar 

  19. Murphy, J., Summer, R., Wilson, A. A., Kotton, D. N. & Fine, A. The prolonged life-span of alveolar macrophages. Am. J. Respir. Cell Mol. Biol. 38, 380–385 (2008)

    CAS  Article  Google Scholar 

  20. Porter, G. A. et al. Significance of plasma cytokine levels in melanoma patients with histologically negative sentinel lymph nodes. Ann. Surg. Oncol. 8, 116–122 (2001)

    CAS  Article  Google Scholar 

  21. Meyskens, F. L., Jr et al. Randomized trial of adjuvant human interferon gamma versus observation in high-risk cutaneous melanoma: a Southwest Oncology Group study. J. Natl. Cancer Inst. 87, 1710–1713 (1995)

    Article  Google Scholar 

  22. Ascierto, P. A. & Kirkwood, J. M. Adjuvant therapy of melanoma with interferon: lessons of the past decade. J. Transl. Med. 6, 62 (2008)

    Article  Google Scholar 

  23. Rebmann, V., Wagner, S. & Grosse-Wilde, H. HLA-G expression in malignant melanoma. Semin. Cancer Biol. 17, 422–429 (2007)

    CAS  Article  Google Scholar 

  24. Derre, L. et al. Expression and release of HLA-E by melanoma cells and melanocytes: potential impact on the response of cytotoxic effector cells. J. Immunol. 177, 3100–3107 (2006)

    CAS  Article  Google Scholar 

  25. Lee, N. et al. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl Acad. Sci. USA 95, 5199–5204 (1998)

    ADS  CAS  Article  Google Scholar 

  26. Wischhusen, J., Waschbisch, A. & Wiendl, H. Immune-refractory cancers and their little helpers—an extended role for immunetolerogenic MHC molecules HLA-G and HLA-E? Semin. Cancer Biol. 17, 459–468 (2007)

    CAS  Article  Google Scholar 

  27. Chen, Z., Koralov, S. B. & Kelsoe, G. Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J. Exp. Med. 192, 1339–1352 (2000)

    CAS  Article  Google Scholar 

  28. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010)

    CAS  Article  Google Scholar 

  29. Shah, K. V., Chien, A. J., Yee, C. & Moon, R. T. CTLA-4 is a direct target of Wnt/β-catenin signaling and is expressed in human melanoma tumors. J. Invest. Dermatol. 128, 2870–2879 (2008)

    CAS  Article  Google Scholar 

  30. Wolnicka-Glubisz, A., King, W. & Noonan, F. P. SCA-1+ cells with an adipocyte phenotype in neonatal mouse skin. J. Invest. Dermatol. 125, 383–385 (2005)

    CAS  Article  Google Scholar 

  31. Budd, P. S. & Jackson, I. J. Structure of the mouse tyrosinase-related protein-2/dopachrome tautomerase (Tyrp2/Dct) gene and sequence of two novel slaty alleles. Genomics 29, 35–43 (1995)

    CAS  Article  Google Scholar 

  32. Urlinger, S. et al. Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc. Natl Acad. Sci. USA 97, 7963–7968 (2000)

    ADS  CAS  Article  Google Scholar 

  33. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004)

    ADS  CAS  Article  Google Scholar 

  34. De Fabo, E. C., Noonan, F. P. & Frederick, J. E. Biologically effective doses of sunlight for immune suppression at various latitudes and their relationship to changes in stratospheric ozone. Photochem. Photobiol. 52, 811–817 (1990)

    CAS  Article  Google Scholar 

  35. Serrano, M. A., Canada, J. & Moreno, J. C. Erythemal ultraviolet exposure of cyclists in Valencia, Spain. Photochem. Photobiol. 86, 716–721 (2010)

    CAS  Article  Google Scholar 

  36. Team, R. D. C. R: A Language and Environment for Statistical Computing. (R Foundation for Statistical Computing, 2008)

    Google Scholar 

  37. Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004)

    Article  Google Scholar 

  38. Du, P., Kibbe, W. A. & Lin, S. M. lumi: a pipeline for processing Illumina microarray. Bioinformatics 24, 1547–1548 (2008)

    CAS  Article  Google Scholar 

  39. Gentleman, R. Bioinformatics and Computational Biology Solutions using R and Bioconductor (Springer, 2005)

    Book  Google Scholar 

  40. Cherwinski, H. M., Schumacher, J. H., Brown, K. D. & Mosmann, T. R. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J. Exp. Med. 166, 1229–1244 (1987)

    CAS  Article  Google Scholar 

  41. Sheehan, K. C. et al. Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. J. Interferon Cytokine Res. 26, 804–819 (2006)

    CAS  Article  Google Scholar 

  42. Goldszmid, R. S. et al. TAP-1 indirectly regulates CD4+ T cell priming in Toxoplasma gondii infection by controlling NK cell IFN-γ production. J. Exp. Med. 204, 2591–2602 (2007)

    CAS  Article  Google Scholar 

  43. Gramzinski, R. A. et al. Interleukin-12- and gamma interferon-dependent protection against malaria conferred by CpG oligodeoxynucleotide in mice. Infect. Immun. 69, 1643–1649 (2001)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding authors

Correspondence to Edward C. De Fabo or Glenn Merlino.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-26 with legends and Supplementary Tables 1-3. (PDF 4164 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zaidi, M., Davis, S., Noonan, F. et al. Interferon-γ links ultraviolet radiation to melanomagenesis in mice. Nature 469, 548–553 (2011). https://doi.org/10.1038/nature09666

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09666

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing