Research

Sequential gene profiling of basal cell carcinomas treated with imiquimod in a placebo-controlled study defines the requirements for tissue rejection

Monica C Panelli¹ , Mitchell E Stashower² , Herbert B Slade³ , Kina Smith¹ , Christopher Norwood⁴ , Andrea Abati⁵ , Patricia Fetsch⁵ , Armando Filie⁵ , Shelley-Ann Walters³ , Calvin Astry³ , Eleonora Aricó¹ , Yingdong Zhao⁶ , Silvia Selleri^1,7 , Ena Wang¹ and Francesco M Marincola¹

¹Immunogenetics Section, Department of Transfusion Medicine, Clinical Center National Institutes of Health, Bethesda, MD 20892, USA

²The Clinical Skin Center of Northern Virginia, Fairfax, VA 22033, USA

³3M Pharmaceuticals, St Paul, MN 55144-1000, USA

⁴Department of Dermatology, National Naval Medical Center, Bethesda, MD 20889, USA

⁵Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA

⁶Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA

⁷Universita' degli Studi di Milano, Department of Human Morphology, via Mangiagalli, 20133 Milan, Italy

author email corresponding author email

Genome Biology 2007, 8:R8doi:10.1186/gb-2007-8-1-r8

Published:	15 January 2007

Subject areas: Cancer, Immunology

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 × 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-α 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.

Conclusion

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.