Gene Expression Profiling Reveals Similarities between the In vitro and In vivo Responses of Immune Effector Cells to IFN-α

Purpose: The precise molecular targets of IFN-α therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patie...

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Bibliographic Details
Published in:Clinical cancer research 2008-09, Vol.14 (18), p.5900-5906
Main Authors: ZIMMERER, Jason M, LESINSKI, Gregory B, RUPPERT, Amy S, RADMACHER, Michael D, NOBLE, Carl, KENDRA, Kari, WALKER, Michael J, CARSON, William E
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Blood Donors
Female
Gene Expression Profiling
Humans
IFN-α
Interferon-alpha - pharmacology
Interferon-alpha - therapeutic use
Killer Cells, Natural - immunology
Leukocytes, Mononuclear - immunology
Male
malignant melanoma
Medical sciences
Melanoma - drug therapy
Melanoma - immunology
Microarray Analysis
monocyte
Monocytes - immunology
natural killer cell
oligonucleotide microarray analysis
Pharmacology. Drug treatments
Recombinant Proteins
T cell
T-Lymphocytes - immunology
Transcriptional Activation
Up-Regulation
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Summary:Purpose: The precise molecular targets of IFN-α therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-α would be similar to the in vivo response to treatment with high-dose IFN-α. Experimental Design: The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-α were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-α. Results: Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-α in vitro for 18 hours (>2-fold, P < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-α–treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients ( n = 13) receiving high-dose IFN-α-2b (20 MU/m 2 i.v.) revealed significant up-regulation (>2-fold) of 21 genes ( P < 0.001). Also, the gene expression profile of in vitro IFN-α–stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-α therapy. Conclusions: This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-α and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-α immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-α may be a useful predictor of the in vivo response of immune cells to IFN-α immunotherapy.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-08-0846