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

• Published in: PLoS medicine Vol. 4; no. 5; p. e176
• Main Authors: Critchley-Thorne, Rebecca J, Yan, Ning, Nacu, Serban, Weber, Jeffrey, Holmes, Susan P, Lee, Peter P
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-05-2007; Public Library of Science (PLoS)
• Subjects: Antigens; Antigens, CD - genetics; Biomarkers; Care and treatment; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Survival - drug effects; Cell Survival - immunology; Computational Biology; Confidence intervals; Cytokines; Down-Regulation - immunology; Furans; Gene expression; Genetic aspects; Genetics; Genetics and Genomics; Health aspects; Humans; Immune system; Immunologic Factors - immunology; Immunologic Factors - pharmacology; Immunology; Immunology and Allergy; Immunotherapy; In Vitro Techniques; Interferon; Interferon-alpha - immunology; Interferon-alpha - pharmacology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lymphocytes; Mathematics; Medical research; Medicine, Experimental; Melanoma; Melanoma - immunology; Melanoma - metabolism; Melanoma - secondary; Metastasis; Oligonucleotide Array Sequence Analysis; Oncology; Patients; Phosphorylation; Proteins; Signal Transduction - drug effects; Signal Transduction - immunology; Skin cancer; Skin Neoplasms - immunology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; STAT1 Transcription Factor - metabolism; T cells; Thiophenes; Tumors; Tyrosine - metabolism; United States; United States > US; Tyrosine; Immunologic Factors; Phosphorylation; Killer Cells, Natural; Oligonucleotide Array Sequence Analysis; Signal Transduction; Biological Markers; Cell Survival; Interferon-alpha; Down-Regulation; Humans; Melanoma; CD8-Positive T-Lymphocytes; Thiophenes; Immunotherapy; Skin Neoplasms; STAT1 Transcription Factor; CD4-Positive T-Lymphocytes; Furans; Antigens, CD
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.0040176

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.