Imiquimod treatment induces expression of opioid growth factor receptor: a novel tumor antigen induced by interferon-alpha?
OBJECTIVE
Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-alpha.


METHODS
To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays.


RESULTS
We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-alpha or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-alpha-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P = 0.041).


CONCLUSIONS
In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens.
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Mirjana
M
Urosevic
Patrick A
PA
Oberholzer
Tanja
T
Maier
Jürg
J
Hafner
Elisabeth
E
Laine
Herbert
H
Slade
Bernd
B
Benninghoff
Günter
G
Burg
Reinhard
R
Dummer
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077271:Imiquimod; D015151:Immunoblotting; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D011956:Receptors, Cell Surface / Q000378:metabolism; D011957:Receptors, Opioid / Q000096:biosynthesis*; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D016896:Treatment Outcome; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011957:Receptors, Opioid; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; C033593:methionine-enkephalin receptor; D000077271:Imiquimod