title: Imiquimod attenuates the growth of UVB-induced SCC in mice through Th1/Th17 cells.
abstract: 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 wk of UVB irradiation, while wild-type mice required much higher doses of UVB with more than 25 wk 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.
authors.affiliation: Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Yokogawa
authors.forename: Mikiro
authors.initials: M
authors.lastname: Takaishi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Nakajima
authors.forename: Reiko
authors.initials: R
authors.lastname: Kamijima
authors.forename: John
authors.initials: J
authors.lastname: Digiovanni
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sano
mesh_terms: D000287:Administration, Topical; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000077271:Imiquimod; D007124:Immunoenzyme Techniques; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000502:physiology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D016207:Cytokines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000077271:Imiquimod