Mechanisms underlying imiquimod-induced regression of basal cell carcinoma in vivo.
BACKGROUND
Imiquimod is a local immune response modifier that has demonstrated potent antiviral and antitumor activity. It enhances innate and acquired immune responses via endogenous cytokine production and has proven efficacious in clearing superficial basal cell carcinoma (sBCC).


OBJECTIVE
To evaluate the mechanisms by which topical imiquimod treatment leads to sBCC clearance in vivo.


METHODS
A pilot, open-label, nonrandomized study.


METHODS
Zurich, Switzerland.


METHODS
Six persons 18 years or older who had nonrecurrent primary tumors that had not undergone previous biopsy or treatment but were suitable for treatment by surgical excision. The tumors were located on the scalp, extremities, or trunk; had a minimum diameter of 1 cm and a maximum diameter of 2 cm; and were clinically and histologically consistent with sBCC.


METHODS
Daily application of 5% imiquimod cream 5 times per week for a maximum of 6 weeks. When the tumor began to show signs of erosion, it was surgically excised.


METHODS
Parameters reflecting tumor apoptotic status (Bcl-2), expression of death receptors (Fas and Fas ligand [FasL]), intercellular adhesion molecule (ICAM) 1, immunosuppressive microenvironment (interleukin 10), and antigen presentation machinery (transporter associated with antigen presentation [TAP] 1) before and after imiquimod treatment were evaluated. The changes in the interferon gamma messenger RNA (mRNA) levels relative to CD4 and CD8 mRNA were assessed using quantitative polymerase chain reaction.


RESULTS
Tumor cells became more susceptible to apoptosis through decreased Bcl-2 expression after treatment with 5% imiquimod cream. Inflammatory infiltrate developed rapidly (within 3 to 5 days after treatment initiation) and was associated with the enhanced expression of ICAM-1. This early response tended to be a mixed cellular response of macrophages and lymphocytes. Interferon gamma was produced by CD4 and CD8 T cells. Imiquimod treatment induced a massive increase in macrophage peritumoral and intratumoral infiltration. Interleukin 10 was produced by infiltrating cells but was not produced by tumor cells. Tumor expression of TAP-1 and Fas/FasL appeared to be unaffected in the first 5 days of treatment.
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Mirjana
M
Urosevic
Tanja
T
Maier
Bernd
B
Benninghoff
Herbert
H
Slade
Guenter
G
Burg
Reinhard
R
Dummer
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000287:Administration, Topical; D000328:Adult; D000634:Aminoquinolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D053222:Fas Ligand Protein; D019254:Genes, bcl-2; D006801:Humans; D000077271:Imiquimod; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D010865:Pilot Projects; D012074:Remission Induction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D019014:fas Receptor / Q000378:metabolism
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; C073119:TAP1 protein, human; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D000077271:Imiquimod