Imiquimod Enhances IFN-γ Production and Effector Function of T Cells Infiltrating Human Squamous Cell Carcinomas of the Skin

• Published in: Journal of investigative dermatology Vol. 129; no. 11; pp. 2676 - 2685
• Main Authors: Huang, Susan J., Hijnen, Dirkjan, Murphy, George F., Kupper, Thomas S., Calarese, Adam W., Mollet, Ilse G., Schanbacher, Carl F., Miller, Danielle M., Schmults, Chrysalyne D., Clark, Rachael A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.11.2009; Nature Publishing Group
• Subjects: Aminoquinolines - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - immunology; Biological and medical sciences; Biopsy; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Division - drug effects; Cell Division - immunology; Dermatology; Granzymes - metabolism; Humans; In Vitro Techniques; Interferon-gamma - metabolism; Interleukin-10 - metabolism; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Medical sciences; Perforin; Pore Forming Cytotoxic Proteins - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Transforming Growth Factor beta - metabolism; Tumors of the skin and soft tissue. Premalignant lesions; Human; Immunomodulator; Skin disease; Squamous cell carcinoma; Basal cell carcinoma; Dermatology; Imiquimod; T-Lymphocyte; Antiviral; Skin; Malignant tumor; Cancer
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2009.151

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-γ, granzyme, and perforin and less IL-10 and transforming growth factor-β (TGF-β) 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-γ, 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.