Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells.
Imiquimod (IMQ), a synthetic agonist to Toll-like receptor (TLR) 7, is being successfully used for the treatment of certain skin neoplasms, but the exact mechanisms by which this compound induces tumor regression are not yet understood. While treating basal cell carcinoma (BCC) patients with topical IMQ, we detected, by immunohistochemistry, sizable numbers of both myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) within the inflammatory infiltrate. Surprisingly, peritumoral mDCs stained positive for perforin and granzyme B, whereas infiltrating pDCs expressed tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The biological relevance of this observation can be deduced from our further findings that peripheral blood-derived CD11c(+) mDCs acquired antiperforin and anti-granzyme B reactivity upon TLR7/8 stimulation and could use these molecules to effectively lyse major histocompatibility complex (MHC) class I(lo) cancer cell lines. The same activation protocol led pDCs to kill MHC class I-bearing Jurkat cells in a TRAIL-dependent fashion. While suggesting that mDCs and pDCs are directly involved in the IMQ-induced destruction of BCC lesions, our data also add a new facet to the functional spectrum of DCs, ascribing to them a major role not only in the initiation but also in the effector phase of the immune response.
Stary
Georg
G
Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, 1090 Vienna, Austria.
Bangert
Christine
C
Tauber
Martina
M
Strohal
Robert
R
Kopp
Tamara
T
Stingl
Georg
G
D000368:Aged; D000369:Aged, 80 and over; D000634:Aminoquinolines / Q000378:metabolism / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000276:immunology; D006801:Humans; D000077271:Imiquimod; D007150:Immunohistochemistry; D007962:Leukocytes / Q000737:chemistry; D008297:Male; D054353:Perforin / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
D000634:Aminoquinolines; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D054353:Perforin; D053804:Granzymes; D000077271:Imiquimod