Imiquimod attenuates the growth of UVB-induced SCC in mice through Th1/Th17 cells.
Imiquimod attenuates the growth of UVB-induced SCC in mice through Th1/Th17 cells.
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DOI：
10.1002/mc.21901
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发表时间：
2013-10
影响因子：
4.6
通讯作者：
Sano, Shigetoshi
中科院分区：
文献类型：
--
作者：
Yokogawa, Maki;Takaishi, Mikiro;Nakajima, Kimiko;Kamijima, Reiko;DiGiovanni, John;Sano, Shigetoshi
咪喹莫特（IMQ），Toll样受体（TLR）7/8激动剂，已被用于治疗各种皮肤肿瘤，包括生殖器疣，光化性角化病和浅表基底细胞癌。尽管已经认识到IMQ激活先天性和适应性免疫，但IMQ在体内发挥其抗肿瘤活性的潜在机制在很大程度上仍然未知。在这项研究中，我们利用皮肤癌易感小鼠的特点，IMQ对紫外线照射（UV）诱导的从头致癌作用的影响。角质形成细胞表达组成型激活的Stat 3的转基因小鼠（K5.Stat3C小鼠）早在UVB照射14周后就发生了鳞状细胞癌（原位SCC），而野生型小鼠需要更高剂量的UVB照射超过25周才能产生SCC。用IMQ局部治疗K5.Stat3C小鼠减弱UVB诱导的表皮发育不良（原位SCC）。此外，SCC的增长，由于增加总照射剂量显着衰减IMQ治疗。局部IMQ治疗诱导肿瘤部位的T细胞和浆细胞样树突状细胞浸润，其中IL-12/23 p40、IL-12 p35、IL-23 p19、IL-17 A和IFN-γ mRNA水平上调。免疫组化显示T细胞浸润由T1、Th 17和CD 8 + T细胞组成。我们推测，局部IMQ治疗减弱UVB诱导的SCC从头生长通过激活的Th 17/Th 1细胞和细胞毒性T淋巴细胞。
Imiquimod (IMQ), a Toll-like receptor (TLR) 7/8 agonist, has been used to treat various skin neoplasms, including genital warts, actinic keratoses and superficial basal cell carcinomas. Although IMQ has been recognized to activate both innate and adaptive immunity, the underlying mechanism(s) by which IMQ exerts its anti-tumor activity in vivo remains largely unknown. In this study, we took advantage of skin cancer-prone mice to characterize the effects of IMQ on ultraviolet irradiation (UV)-induced de novo carcinogenesis. Transgenic mice with keratinocytes expressing constitutively activated Stat3 (K5.Stat3C mice) developed squamous cell carcinomas (SCC in situ) as early as after 14 weeks of UVB irradiation, while wild-type mice required much higher doses of UVB with more than 25 weeks of UVB irradiation to produce SCC. Topical treatment of K5.Stat3C mice with IMQ attenuated UVB-induced epidermal dysplasia (SCC in situ). In addition, SCC growth due to increased total irradiation doses was significantly attenuated by IMQ treatment. Topical IMQ treatment induced T cell and plasmacytoid dendritic cell infiltrates at the tumor sites, where levels of IL-12/23p40, IL-12p35, IL-23p19, IL-17A and IFN-γ mRNAs were up-regulated. Immunohistochemistry revealed T cell infiltrates consisting of T1, Th17 and CD8+ T cells. We speculate that topical IMQ treatment attenuates the de novo growth of UVB-induced SCC through activation of Th17/Th1 cells and cytotoxic T lymphocytes.
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影响因子：
8
作者：
Maniati, E.;Soper, R.;Hagemann, T.
通讯作者：
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