1. ¹Harvard Skin Disease Research Center and the Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
2. ²Department of Dermatology, Utrecht University Medical Center, Utrecht, The Netherlands
3. ³Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
4. ⁴Department of Dermatology, Ghent University Hospital, Gent, Belgium

Correspondence: Dr Rachael A. Clark, Department of Dermatology, Brigham and Women's Hospital, EBRC Room 505A, 221 Longwood Avenue, Boston, Massachusetts 02115, USA. E-mail: rclark1@partners.org

Received 23 July 2008; Revised 9 March 2009; Accepted 3 April 2009; Published online 11 June 2009.

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