Enhanced type I interferon signaling and recruitment of chemokine receptor CXCR3-expressing lymphocytes into the skin following treatment with the TLR7-agonist imiquimod.
BACKGROUND
Imiquimod (Aldara) 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) alpha, which is able to enhance Th1-mediated cellular antiviral and antitumor immunity.


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.


CONCLUSIONS
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
Joerg
J
Department of Dermatology, University of Bonn, Bonn, Germany. joerg.wenzel@ukb.uni-bonn.de
Uerlich
Manfred
M
Haller
Otto
O
Bieber
Thomas
T
Tueting
Thomas
T
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000634:Aminoquinolines / Q000276:immunology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000276:immunology / Q000556:secondary; D002280:Basal Cell Carcinoma / Q000276:immunology / Q000556:secondary; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D000077271:Imiquimod; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000556:secondary; D008562:Membrane Glycoproteins / Q000819:agonists*; D054367:Receptors, CXCR3; D011956:Receptors, Cell Surface / Q000819:agonists*; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000276:immunology*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000556:secondary; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; C515187:CXCR3 protein, human; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D054367:Receptors, CXCR3; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D000077271:Imiquimod