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PMID: 17488182 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma.

PLoS medicine ·Vol. 4 ·No. 5 ·2007-05-00 ·Pages e176

Critchley-Thorne RJ, Yan N, Nacu S, Weber J, Holmes SP, Lee PP

Abstract

Dysfunction of the immune system has been documented in many types of cancers. The precise nature and molecular basis of immune dysfunction in the cancer state are not well defined. To gain insights into the molecular mechanisms of immune dysfunction in cancer, gene expression profiles of pure sorted peripheral blood lymphocytes from 12 patients with melanoma were compared to 12 healthy controls. Of 25 significantly altered genes in T cells and B cells from melanoma patients, 17 are interferon (IFN)-stimulated genes. These microarray findings were further confirmed by quantitative PCR and functional responses to IFNs. The median percentage of lymphocytes that phosphorylate STAT1 in response to interferon-alpha was significantly reduced (Delta = 16.8%; 95% confidence interval, 0.98% to 33.35%) in melanoma patients (n = 9) compared to healthy controls (n = 9) in Phosflow analysis. The Phosflow results also identified two subgroups of patients with melanoma: IFN-responsive (33%) and low-IFN-response (66%). The defect in IFN signaling in the melanoma patient group as a whole was partially overcome at the level of expression of IFN-stimulated genes by prolonged stimulation with the high concentration of IFN-alpha that is achievable only in IFN therapy used in melanoma. The lowest responders to IFN-alpha in the Phosflow assay also showed the lowest gene expression in response to IFN-alpha. Finally, T cells from low-IFN-response patients exhibited functional abnormalities, including decreased expression of activation markers CD69, CD25, and CD71; TH1 cytokines interleukin-2, IFN-gamma, and tumor necrosis factor alpha, and reduced survival following stimulation with anti-CD3/CD28 antibodies compared to controls. Defects in interferon signaling represent novel, dominant mechanisms of immune dysfunction in cancer. These findings may be used to design therapies to counteract immune dysfunction in melanoma and to improve cancer immunotherapy.

MeSH Terms
Antigens, CD/genetics Biomarkers CD4-Positive T-Lymphocytes/drug effects,immunology CD8-Positive T-Lymphocytes/drug effects,immunology Cell Survival/drug effects,immunology Down-Regulation/immunology Furans Humans Immunologic Factors/immunology,pharmacology Immunotherapy In Vitro Techniques Interferon-alpha/immunology,pharmacology Killer Cells, Natural/drug effects,immunology Melanoma/immunology,metabolism,secondary Oligonucleotide Array Sequence Analysis Phosphorylation STAT1 Transcription Factor/metabolism Signal Transduction/drug effects,immunology Skin Neoplasms/immunology,metabolism,pathology Thiophenes Tyrosine/metabolism
Chemicals
3,4-bis-(2,4,5-trimethyl-thiophen-3-yl)furan-2,5-dione Antigens, CD Biomarkers Furans Immunologic Factors Interferon-alpha STAT1 Transcription Factor STAT1 protein, human Thiophenes Tyrosine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Critchley-Thorne Rebecca J
Division of Hematology, Department of Medicine, Stanford University, Stanford, California, United States of America.
Yan Ning
Nacu Serban
Weber Jeffrey
Holmes Susan P
Lee Peter P
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Article Info
Journal
PLoS medicine
Abbr.
PLoS Med
ISSN
1549-1676
DOI
10.1371/journal.pmed.0040176
Published
2007-05-00
Pages
e176
Language
English
Region
United States
NLM ID
101231360
PMCID
PMC1865558
Subset
IM
Grants
NCI NIH HHS · R01 CA090809 · United States
NCI NIH HHS · R01 CA 090809 · United States
Databases
GEO
GSE6887
External Links
PubMed source DOI: 10.1371/journal.pmed.0040176 PMC Full Text View journal details
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