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大学・研究所にある論文を検索できる 「Increased expression of dermal LL-37 may trigger migration of CCR-7+regulatory T cells in extramammary Paget’s disease」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
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Increased expression of dermal LL-37 may trigger migration of CCR-7+regulatory T cells in extramammary Paget’s disease

LYU CHUNBING 東北大学

2021.03.25

概要

Background
Since extramammary Paget’s disease (EMPD) is a skin adenocarcinoma of apocrine gland origin, the biological behavior of EMPD is similar to that of breast cancer. Invasive EMPD frequently metastasizes to lymph nodes, liver, lung and even brain. Therefore, an appropriate marker to distinguish in situ from dermal invasive EMPD in the early stage is needed. Since dermal LL-37 expression is augmented by stimulation with IL-17, and since Paget’s cells produce CCL-20 to recruit Th17 in the lesional skin of EMPD, in this report, we hypothesized that LL-37 in the dermis is augmented in invasive EMPD.

Methods
We first employed immunohistochemical (IHC) staining of LL-37 in 15 cases of invasive and 11 cases non-invasive EMPD to evaluate the expression levels of LL-37 by digital microscope. Next, to evaluate the immunomodulatory effects of LL-37 on tumor- associated macrophages (TAMs) distributed in the dermis of the lesional skin of EMPD, we stimulated monocyte-derived M2 macrophages by LL-37 and measured the production of immunosuppressive chemokines using ELISA in vitro. Then, we further evaluated the serum level of these chemokine of EMPD patients.

Results
Quantitative analysis of IHC staining revealed that LL-37-expressing myeloid cells in dermis were significantly more in invasive EMPD than in non-invasive EMPD. Moreover, CD163+M2 macrophages produced CCL-19 and CCL-21 by LL-37 stimulation in vitro, suggesting that these chemokines might be produced by CD163+TAMs to recruit CCR- 7+regulatory T cells in the lesional skin of invasive EMPD. Indeed, immunofluorescence staining (IF) and IHC staining showed that substantial numbers of CD163+TAMs expressed CCL-19 and CCL-21 in the lesional skin of invasive EMPD. In addition, IHC staining revealed that CCR-7 positive cells (including regulatory T cells) were located within lymphatic vessels in the lesional skin of invasive EMPD. Furthermore, the serum levels of CCL-19 and CCL-21 were significantly increased in invasive EMPD patients compared to non-invasive EMPD patients.

Conclusion
The present study shows that TAMs around lymphatic vessels or small blood vessels produce LL-37 that stimulate the production of CCL-19 and CCL-21. These chemokines recruit CCR-7 +Tregs, which may play a role in the development of immunosuppressive microenvironment of invasive EMPD. These results suggest the potential of IL-17 blockade therapy to restore the immunosuppressive environment.

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