Impaired STAT phosphorylation in T cells from melanoma patients in response to IL-2: Association with clinical stage

Roberta Mortarini, Claudia Vegetti, Alessandra Molla, Flavio Arienti, Fernando Ravagnani, Andrea Maurichi, Roberto Patuzzo, Mario Santinami, Andrea Anichini

Research output: Contribution to journalArticlepeer-review

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. 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 activationin 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 β1 counteracted such inhibition. 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.

Original languageEnglish
Pages (from-to)4085-4094
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number12
DOIs
Publication statusPublished - Jun 15 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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