Epidermal 伪6尾4 integrin stimulates the influx of immunosuppressive cells during skin tumor promotion

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• 作者：Samar W. Maalouf^a ; Surein Theivakumar^b ; David M. Owens^a ; ^c ; ^{do2112@columbia.edu}
• 关键词：Skin carcinogenesis ; Myeloid-derived suppressor cell ; Microenvironment ; Squamous cell carcinoma ; Keratinocyte
• 刊名：Journal of Dermatological Science
• 出版年：2012
• 期刊代码：153_09231811
• 类别：med
• 出版时间：May, 2012
• 卷：66
• 期：2
• 页码：108-118
• 文件大小：3317 K

摘要

Background

Induction of 伪6尾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伪6尾4 transgenic mice, which exhibit persistent expression of 伪6尾4 in the suprabasal epidermal layers. However, the molecular basis for the support of SCC development by suprabasal 伪6尾4 is not fully understood.

Objective

We examined the relevance for suprabasal 伪6尾4 expression in the epidermis for the recruitment of immunosuppressive leukocytes during the early stages of tumor promotion.

Methods

In this study, we made use of the Inv伪6尾4 transgenic mouse model, which exhibits expression of 伪6尾4 integrin in the suprabasal layers of the epidermis driven by the involucrin promoter. First, we examined protein lysates from Inv伪6尾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伪6尾4 transgenic skin. Finally, a macrophage colony stimulating factor (M-CSF) neutralizing antibody strategy was administered to resolve Inv伪6尾4 transgenic skin inflammation.

Results

Employing the Inv伪6尾4 transgenic mouse model, we show that suprabasal 伪6尾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伪6尾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伪6尾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伪6尾4 mice treated with M-CSF neutralizing antibodies.

Conclusions

We conclude that aberrant expression of 伪6尾4 integrin in post-mitotic epidermal keratinocytes stimulates a pro-tumorigenic skin microenvironment by augmenting the influx of immunosuppressive granular cells during tumor promotion.