Imiquimod enhances IFN-gamma production and effector function of T cells infiltrating human squamous cell carcinomas of the skin.
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.
Huang
Susan J
SJ
Harvard Skin Disease Research Center and the Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Hijnen
Dirkjan
D
Murphy
George F
GF
Kupper
Thomas S
TS
Calarese
Adam W
AW
Mollet
Ilse G
IG
Schanbacher
Carl F
CF
Miller
Danielle M
DM
Schmults
Chrysalyne D
CD
Clark
Rachael A
RA
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
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