Abstract
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. 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. 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.
Highlights
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
By looking at phosphorylation of STAT1 and STAT5 proteins, a key signaling event triggered by IL-2, evidence for defective responsiveness to this cytokine was found in T cells from peripheral blood or tumor site of American Joint Committee on Cancer Stage III and IV patients, compared to stage I and II patients and to normal donors
Reduced proliferative response to IL-2 and IL-15 in T cells from advanced melanoma patients compared with healthy donors
Summary
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. By looking at phosphorylation of STAT1 and STAT5 proteins, a key signaling event triggered by IL-2, evidence for defective responsiveness to this cytokine was found in T cells from peripheral blood or tumor site of American Joint Committee on Cancer Stage III and IV patients, compared to stage I and II patients and to normal donors These results indicate that melanoma progression is associated with development of immune dysfunction affecting the g chain cytokine signaling pathway. These findings suggest that assessment of STAT phosphorylation at the single-cell level by phospho ^ flow cytometry may be an effective approach to identify patients with retained responsiveness to cytokines as IL-2. Reactive IL-2Ra-/- CD8+ T cells fail to control established tumors [14] and that IL-15 and IL-21 have cooperative effects in CD8+mediated tumor regression [12]
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