Enhanced type I interferon signaling and recruitment of chemokine receptor CXCR3-expressing lymphocytes into the skin following treatment with the TLR7-agonist imiquimod Joerg Wenzel 1 , Manfred Uerlich 1 , Otto Haller 2 , Thomas Bieber 1 and Thomas Tueting 1 1 Department of Dermatology, University of Bonn, and 2 Department of Virology, Institute of Medical Microbiology und Hygiene, University of Freiburg, Germany Joerg Wenzel, MD, Department of Dermatology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany Tel: þ49 228 287 5370 Fax: þ49 228 287 4333 e-mail: joerg.wenzel@ukb.uni-bonn.de Accepted August 17, 2004 Introduction: Imiquimod (Aldara TM ) is an immune response modifier approved for the topical treatment of external genital and perianal warts which can mediate regression of several cutaneous malignancies [basal cell carcinoma (BCC), Bowen’s disease, actinic keratosis, and metastasis of malignant melanoma]. Recently, it was discovered that imiquimod acts through the toll-like receptor (TLR) 7. We hypothesize that TLR7- signaling strongly induces the production of interferon (IFN) a, which is able to enhance Th1-mediated cellular antiviral and antitumor immunity. Patients and methods: In the present study we analyzed the expression of MxA, a protein specifically induced by type I IFNs during topical imiquimod treatment in several patients suffering from different cutaneous malignancies (BCC, cutaneous metastasis of melanoma, and breast cancer), and characterized the inflammatory infiltrate, along with the expression of chemokine receptor CXCR3, by immunohistochemistry. Results: Treatment with the TLR7-agonist imiquimod induced a significant lesional lymphocytic inflammation, associated with strong expression of MxA, indicating the induction of type I IFN signaling. The extent of lesional MxA staining closely correlated with the number of infiltrating T lymphocytes and the expression of the chemokine receptor CXCR3, characteristic for Th1-biased immune responses. Discussion: Our in vivo results suggest an important role for TLR7- induced production of type I IFN, which links innate and adaptive immunity and promotes specific Th1-biased cellular immune response capable of eliminating cutaneous malignancies. MxA appears to be a valuable parameter to demonstrate IFN-type I expression in imiquimod therapy. Wenzel J, Uerlich M, Haller O, Bieber T, Tueting T. Enhanced type I interferon signaling and recruitment of chemokine receptor CXCR3 expressing lymphocytes into the skin following treatment with the TLR7-agonist imiquimod. J Cutan Pathol 2005; 32: 257–262. # Blackwell Munksgaard 2005. Imiquimod is an immune response modifier with potent antiviral and antitumor activity. The agent is an imidazoquinoline amine that is able to up-regulate innate and acquired immunity by induction of type I interferons (IFNs) and other inflammatory cytokines. It was approved by the U.S. Food and Drug J Cutan Pathol 2005: 32: 257–262 Copyright # Blackwell Munksgaard 2005 Blackwell Munksgaard. Printed in Denmark Journal of Cutaneous Pathology 257