Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment.
BACKGROUND
Imiquimod, an immune response modifier that is used topically to treat different types of skin cancer, induces the production of proinflammatory cytokines that stimulate an antitumor immune response. We assessed characteristics of the imiquimod-induced immune activation in epithelial and lymphoproliferative neoplasias of human skin. We focused on plasmacytoid predendritic cells (PDCs), the primary producer of interferon alpha (IFN-alpha) after imiquimod activation in vitro.


METHODS
We used Affymetrix oligonucleotide arrays to compare gene expression profiles from tumors from 16 patients, 10 with superficial basal cell carcinomas (sBCCs), five with cutaneous T-cell lymphomas (CTCLs), and one with Bowen's disease, before and after topical imiquimod treatment. We used quantitative immunohistochemistry with PDC-specific antibodies against BDCA-2 and CD123 to characterize the PDC population before and after imiquimod treatment in these specimens. Activation status of PDCs from four sBCC patients was assessed by intracellular IFN-alpha staining and flow cytometry.


RESULTS
Expression of various IFN-alpha-inducible genes (e.g., CIG5, G1P2, OASL, IFIT1, STAT1, IFI35, OAS1, ISG20, MxA, and IRF7), the so-called IFN-alpha signature, was increased similarly in both sBCC and CTCL lesions after imiquimod treatment. PDCs were recruited and activated in both lesion types, and they produced IFN-alpha after imiquimod treatment in vivo (mean percentage of PDCs producing IFN-alpha = 14.5%, 95% confidence interval [CI] = 4.9% to 24%; range = 3.3%-27%, n = 4 lesions). Imiquimod induced similar immune activation patterns in all three diseases, and these patterns were associated with the number of PDCs recruited to the treatment site. Two imiquimod-treated sBCC patients who did not mount an inflammatory response to imiquimod and whose lesions lacked the IFN-alpha signature after treatment had fewer PDCs in treated lesions compared with other treated patients with such a response.


CONCLUSIONS
Imiquimod induces immune activation patterns that relate to the number of the PDCs recruited to the treatment site, thus supporting the role of PDC in responsiveness to imiquimod in humans.
Urosevic
Mirjana
M
Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland. Mirjana.Urosevic@usz.ch
Dummer
Reinhard
R
Conrad
Curdin
C
Beyeler
Mirjam
M
Laine
Elisabeth
E
Burg
Günter
G
Gilliet
Michel
M
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000279:Administration, Cutaneous; D000634:Aminoquinolines / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D001913:Bowen's Disease / Q000188:drug therapy / Q000276:immunology; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000276:immunology; D002986:Clinical Trials as Topic; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077271:Imiquimod; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000378:metabolism*; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000276:immunology; D018613:Microscopy, Confocal; D010950:Plasma Cells / Q000187:drug effects* / Q000276:immunology; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D016898:Interferon-alpha; D000077271:Imiquimod