title: Sequential gene profiling of basal cell carcinomas treated with imiquimod in a placebo-controlled study defines the requirements for tissue rejection.
abstract: BACKGROUND
  Imiquimod is a Toll-like receptor-7 agonist capable of inducing complete clearance of basal cell carcinoma (BCC) and other cutaneous malignancies. We hypothesized that the characterization of the early transcriptional events induced by imiquimod may provide insights about immunological events preceding acute tissue and/or tumor rejection.
  
  
  RESULTS
  We report a paired analysis of adjacent punch biopsies obtained pre- and post-treatment from 36 patients with BCC subjected to local application of imiquimod (n = 22) or vehicle cream (n = 14) in a blinded, randomized protocol. Four treatments were assessed (q12 applications for 2 or 4 days, or q24 hours for 4 or 8 days). RNA was amplified and hybridized to 17.5 K cDNA arrays. All treatment schedules similarly affected the transcriptional profile of BCC; however, the q12 x 4 days regimen, associated with highest effectiveness, induced the most changes, with 637 genes unequivocally stimulated by imiquimod. A minority of transcripts (98 genes) confirmed previous reports of interferon-alpha involvement. The remaining 539 genes portrayed additional immunological functions predominantly involving the activation of cellular innate and adaptive immune-effector mechanisms. Importantly, these effector signatures recapitulate previous observations of tissue rejection in the context of cancer immunotherapy, acute allograft rejection and autoimmunity.
  
  
  CONCLUSIONS
  This study, based on a powerful and reproducible model of cancer eradication by innate immune mechanisms, provides the first insights in humans into the early transcriptional events associated with immune rejection. This model is likely representative of constant immunological pathways through which innate and adaptive immune responses combine to induce tissue destruction.
authors.affiliation: Immunogenetics Section, Department of Transfusion Medicine, Clinical Center National Institutes of Health, Bethesda, MD 20892, USA. mpanelli@mail.cc.nih.gov
authors.forename: Monica C
authors.initials: MC
authors.lastname: Panelli
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Stashower
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Slade
authors.forename: Kina
authors.initials: K
authors.lastname: Smith
authors.forename: Christopher
authors.initials: C
authors.lastname: Norwood
authors.forename: Andrea
authors.initials: A
authors.lastname: Abati
authors.forename: Patricia
authors.initials: P
authors.lastname: Fetsch
authors.forename: Armando
authors.initials: A
authors.lastname: Filie
authors.forename: Shelley-Ann
authors.initials: SA
authors.lastname: Walters
authors.forename: Calvin
authors.initials: C
authors.lastname: Astry
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aricó
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Silvia
authors.initials: S
authors.lastname: Selleri
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019002:CD56 Antigen / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D000077271:Imiquimod; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D010919:Placebos; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D019002:CD56 Antigen; D016827:CD8 Antigens; D016898:Interferon-alpha; D010919:Placebos; D012333:RNA, Messenger; D007371:Interferon-gamma; D000077271:Imiquimod