CLINICAL AND LABORATORY INVESTIGATIONS BJD British Journal of Dermatology Psoralen plus ultraviolet A ± interferon-a treatment resistance in mycosis fungoides: the role of tumour microenvironment, nuclear transcription factor-jB and T-cell receptor pathways M.B. Wozniak, L. Tracey, P.L. Ortiz-Romero,* S. Montes, M. Alvarez,à J. Fraga,§ J. Ferna ´ndez Herrera,– S. Vidal,** J.L. Rodriguez-Peralto, M.A ´ . Piris and R. Villuendas (deceased) Molecular Pathology Program, Centro Nacional de Investigaciones Oncolo´gicas, Madrid, Spain Departments of *Dermatology and  Pathology, Hospital 12 de Octubre, Madrid, Spain àDepartment of Pathology, Hospital Universitario La Paz, Madrid, Spain Departments of §Pathology and –Dermatology, Hospital de la Princesa, Madrid, Spain **Department of Dermatology, Hospital Militar Gomez Ulla, Madrid, Spain Correspondence Miguel A ´ . Piris. Centro Nacional de Investigaciones Oncolo´gicas, Melchor Ferna ´ndez Almagro 3, Madrid 28029, Spain E-mail: mapiris@cnio.es Accepted for publication 19 August 2008 Key words interferon alpha, microarray analysis, microenvironment, mycosis fungoides, psoralen plus ultraviolet A Conflicts of interest None declared. M.B.W. and L.T. contributed equally to this work. DOI 10.1111/j.1365-2133.2008.08886.x Summary Background Interferon (IFN)-a is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients’ resistance to PUVA ± IFN-a treatment. Objectives To identify factors responsible for resistance to PUVA ± IFN-a treatment in MF patients. Patients ⁄ methods The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-a clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identi- fication of genes and biologically significant pathways related to resistance to treatment. Results Genes involved in NF-jB signalling, T-cell receptor (TCR) signalling, cyto- kine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopula- tions of macrophages, dendritic cells and other non-neoplastic cell types consti- tuting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma. Conclusions Gene expression changes in both the tumour and the tumour micro- environment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-jB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment. Mycosis fungoides (MF), a cutaneous T-cell lymphoma, 1 is characterized by infiltration of epidermotropic tumoral T cells in the skin. 2,3 At present, no curative treatment for MF is available, and the currently used therapeutic strategies have failed to show a survival benefit for patients. Psoralen and ultraviolet A phototherapy (PUVA) combines the oral or topical administration of psoralen (to sensitize skin) with exposure to UVA radiation. Generation of reactive oxygen species, inhibition of DNA synthesis and mito- chondrial dysfunction have been proposed as mechanisms of Ó 2008 The Authors 92 Journal Compilation Ó 2008 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp92–102