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-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.
| Original language | English |
|---|---|
| Pages (from-to) | 2676-2685 |
| Number of pages | 10 |
| Journal | Journal of Investigative Dermatology |
| Volume | 129 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2009 |
| Externally published | Yes |
Bibliographical note
Funding Information:The authors thank Dr Thomas Cochran of the Boston Center for Plastic Surgery and Dr Elof Eriksson of Brigham and Women's Hospital for generously providing normal human skin samples; Dr Richard Miller and 3M Pharmaceuticals for kindly providing imiquimod cream and powdered imiquimod; and Dr James Rheinwald for generously providing the SCC13 cell line. This research was supported by NIH Grant 1K08AI060890-01A1, a Translational Research Award from the Leukemia and Lymphoma Society (to R.A.C.), a Pilot & Feasibility grant from the Harvard Skin Disease Research Center (to R.A.C. from NIH Grant P30 AR-42689-11, to T.S.K.), a Developmental project from the SPORE in Skin Cancer (to R.A.C., from NIH Grant P50 CA-93683-04, to T.S.K.), a Clinical Investigator Award from the Damon Runyon Cancer Research Foundation (to R.A.C.), and a Howard Hughes Medical Institute Medical Research Training Fellowship (to S.J.H.).
