Epidermal ?6?4 integrin stimulates the influx of immunosuppressive cells during skin tumor promotion.

ABSTRACT: Induction of ?6?4 integrin in the differentiated epidermal cell layers in skin is a hallmark of human cutaneous squamous cell carcinoma (SCC) pathogenesis and stimulates chemically induced SCC formation in Inv?6?4 transgenic mice, which exhibit persistent expression of ?6?4 in the suprabasal epidermal layers. However, the molecular basis for the support of SCC development by suprabasal ?6?4 is not fully understood.We examined the relevance for suprabasal ?6?4 expression in the epidermis for the recruitment of immunosuppressive leukocytes during the early stages of tumor promotion.In this study, we made use of the Inv?6?4 transgenic mouse model, which exhibits expression of ?6?4 integrin in the suprabasal layers of the epidermis driven by the involucrin promoter. First, we examined protein lysates from Inv?6?4 transgenic skin using a pro-inflammatory cytokine array panel. Next, we immunofluorescence labeling of murine skin sections was employed to immunophenotype tumor promoter-treated Inv?6?4 transgenic skin. Finally, a macrophage colony stimulating factor (M-CSF) neutralizing antibody strategy was administered to resolve Inv?6?4 transgenic skin inflammation.Employing the Inv?6?4 transgenic mouse model, we show that suprabasal ?6?4 integrin expression selectively alters the profile of secreted pro-inflammatory molecules by epidermal cells, in particular CXCL5 and M-CSF, in response to acute tumor promoter treatment. The induction of CXCL5 and M-CSF in Inv?6?4 transgenic epidermis was shortly followed by an exacerbated influx of CD200R(+) myeloid-derived suppressor cells (MDSCs), which co-expressed the M-CSF receptor, and FoxP3(+) Treg cells compared to wild-type mice. As a result, the levels of activated CD4(+) T lymphocytes were dramatically diminished in Inv?6?4 transgenic compared to wild-type skin, whereas similar levels of lymphocyte activation were observed in the peripheral blood. Finally, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced CD200R(+) infiltrative cells and epidermal proliferation were suppressed in Inv?6?4 mice treated with M-CSF neutralizing antibodies.We conclude that aberrant expression of ?6?4 integrin in post-mitotic epidermal keratinocytes stimulates a pro-tumorigenic skin microenvironment by augmenting the influx of immunosuppressive granular cells during tumor promotion.

SUBMITTER: Maalouf SW 

PROVIDER: S-EPMC3328604 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature