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 childhood. 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 UVA. 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.
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
M Raza
MR
Zaidi
Sean
S
Davis
Frances P
FP
Noonan
Cari
C
Graff-Cherry
Teresa S
TS
Hawley
Robert L
RL
Walker
Lionel
L
Feigenbaum
Elaine
E
Fuchs
Lyudmila
L
Lyakh
Howard A
HA
Young
Thomas J
TJ
Hornyak
Heinz
H
Arnheiter
Giorgio
G
Trinchieri
Paul S
PS
Meltzer
Edward C
EC
De Fabo
Glenn
G
Merlino
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000528:radiation effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D008544:Melanocytes / Q000378:metabolism* / Q000528:radiation effects; D008545:Melanoma / Q000503:physiopathology*; D051379:Mice; D014466:Ultraviolet Rays
D007371:Interferon-gamma
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