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Impaired STAT phosphorylation in T cells from melanoma patients in response to IL-2: association with clinical stage.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2009 Jun 15; Vol. 15 (12), pp. 4085-94. Date of Electronic Publication: 2009 Jun 09. - Publication Year :
- 2009
-
Abstract
- Purpose: To assess the extent of signal transducer and activator of transcription (STAT) activation in response to interleukin 2 (IL-2) in melanoma patients' T cells, along with clinical stage of tumor progression.<br />Experimental Design: T lymphocytes from peripheral blood of healthy donors and of American Joint Committee on Cancer stage I to IV melanoma patients, as well as from metastatic lymph nodes of patients, were evaluated for responsiveness to IL-2. CFSE assays and single-cell phospho-STAT-specific flow cytometry screening were used. Results. T cells from advanced melanoma patients, in comparison with healthy donors, showed reduced proliferation to IL-2 and IL-15, but not to anti-CD3 monoclonal antibody. Impaired response occurred in CCR7(+) and CCR7(-) T-cell subsets, but not in CD3(-) CD8(+) natural killer (NK) cells, and was not explained by induction of apoptosis, increased cytokine consumption, or altered IL-2R subunit expression in patients' T lymphocytes. By phospho-specific flow cytometry, defective STAT1 and STAT5 activation in response to IL-2 was found mainly in T lymphocytes from peripheral blood and/or tumor site of American Joint Committee on Cancer stage III and IV patients, compared with stage I and II patients and to donors, and in melanoma antigen-specific T cells isolated from metastatic lymph nodes. At tumor site, impaired STAT activation in T cells did not correlate with frequency of CD4(+) CD25(+) Foxp3(+) T cells. Serum from advanced melanoma patients inhibited IL-2-dependent STAT activation in donors' T cells and a neutralizing monoclonal antibody to transforming growth factor beta1 counteracted such inhibition.<br />Conclusions: These results provide evidence for development of impaired STAT signaling in response to IL-2, along with clinical evolution of the disease, in melanoma patients' T cells.
- Subjects :
- CD3 Complex immunology
CD3 Complex metabolism
Cell Proliferation drug effects
Humans
Interleukin-15 pharmacology
Janus Kinase 3 immunology
Janus Kinase 3 metabolism
Killer Cells, Natural immunology
Killer Cells, Natural metabolism
Melanoma pathology
Neoplasm Staging
Phosphorylation drug effects
Receptors, Cytokine immunology
Receptors, Cytokine metabolism
Skin Neoplasms pathology
T-Lymphocytes metabolism
Interleukin-2 pharmacology
Killer Cells, Natural drug effects
Melanoma immunology
STAT1 Transcription Factor metabolism
STAT5 Transcription Factor metabolism
Skin Neoplasms immunology
T-Lymphocytes drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 15
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 19509154
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-08-3323