title: Imiquimod inhibits melanoma development by promoting pDC cytotoxic functions and impeding tumor vascularization.
abstract: Imiquimod (IMQ) is a synthetic Toll-like receptor (TLR7/8) ligand that can trigger antiviral and antitumor activities. Despite evidence of potent therapeutic effects, the clinical use of IMQ in melanoma is impeded by incomplete understanding of its mechanisms of action. Mice and humans differ in many aspects of immunity, including TLR7 expression patterns, thus impeding the use of mouse models in translating discoveries into clinical applications. In this article, we investigated the mechanisms behind IMQ effects in vivo in a human context of melanoma and immunity using an innovative melanoma-bearing humanized mouse model. In this model, IMQ strongly inhibited melanoma tumor development through prompt mobilization of plasmacytoid dendritic cells and by triggering their cytotoxic functions, and through upregulation of expression of type 1 IFN response genes. IMQ also drastically impeded tumor vascularization by inducing the downregulation of angiogenic factors vascular endothelial growth factor, angiogenin, IL-8, and fibroblast growth factor. Our results revealed the short- and long-term multifactorial effects of IMQ converging toward inhibition of melanoma development. By providing a better understanding of the mechanisms of action of IMQ in melanoma, our study opens the way for its further clinical use in the treatment of metastatic melanoma.
authors.affiliation: R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France. Electronic address: carolineaspord@yahoo.com.
authors.forename: Caroline
authors.initials: C
authors.lastname: Aspord
authors.affiliation: R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Tramcourt
authors.affiliation: R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Leloup
authors.affiliation: R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Molens
authors.affiliation: University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France; Department of Dermatology, Grenoble University Hospital, Grenoble, France.
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Leccia
authors.affiliation: University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France; Department of Dermatology, Grenoble University Hospital, Grenoble, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Charles
authors.affiliation: R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Plumas
mesh_terms: D000287:Administration, Topical; D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D000077271:Imiquimod; D016209:Interleukin-8 / Q000378:metabolism; D008545:Melanoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D000077271:Imiquimod
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