title: Imiquimod enhances IFN-gamma production and effector function of T cells infiltrating human squamous cell carcinomas of the skin.
abstract: Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in patients taking T-cell immunosuppressant medications. Imiquimod is a topical immune response modifier and Toll-like receptor 7 (TLR7) agonist that induces the immunological destruction of SCC and other skin cancers. TLR7 activation by imiquimod has pleiotropic effects on innate immune cells, but its effects on T cells remain largely uncharacterized. Because tumor destruction and formation of immunological memory are ultimately T-cell-mediated effects, we studied the effects of imiquimod therapy on effector T cells infiltrating human SCC. SCC treated with imiquimod before excision contained dense T-cell infiltrates associated with tumor cell apoptosis and histological evidence of tumor regression. Effector T cells from treated SCC produced more IFN-gamma, granzyme, and perforin and less IL-10 and transforming growth factor-beta (TGF-beta) than T cells from untreated tumors. Treatment of normal human skin with imiquimod induced activation of resident T cells and reduced IL-10 production but had no effect on IFN-gamma, perforin, or granzyme, suggesting that these latter effects arise from the recruitment of distinct populations of T cells into tumors. Thus, imiquimod stimulates tumor destruction by recruiting cutaneous effector T cells from blood and by inhibiting tonic anti-inflammatory signals within the tumor.
authors.affiliation: Harvard Skin Disease Research Center and the Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Huang
authors.forename: Dirkjan
authors.initials: D
authors.lastname: Hijnen
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.forename: Adam W
authors.initials: AW
authors.lastname: Calarese
authors.forename: Ilse G
authors.initials: IG
authors.lastname: Mollet
authors.forename: Carl F
authors.initials: CF
authors.lastname: Schanbacher
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Miller
authors.forename: Chrysalyne D
authors.initials: CD
authors.lastname: Schmults
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Clark
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D000077271:Imiquimod; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; C508609:IL10 protein, human; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D016212:Transforming Growth Factor beta; D054353:Perforin; D016753:Interleukin-10; D007371:Interferon-gamma; D053804:Granzymes; D000077271:Imiquimod