Expression and activity of signaling molecules in T lymphocytes obtained from patients with metastatic melanoma before and after interleukin 2 therapy

Hannah Rabinowich, Michael Banks, Torsten E. Reichert, Theodore F. Logan, John M. Kirkwood, Theresa L. Whiteside

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Recent studies have demonstrated altered expression and function of signaling molecules in T and natural killer cells in patients with cancer. The impairment of immune cell functions in advanced cancer may result from defects in signal transduction. We studied purified T cells obtained from peripheral blood or tumor-involved lymph nodes (LNs) of 45 patients with advanced metastatic melanoma for the presence of abnormalities in expression or activity of various signaling molecules. Western blot analyses demonstrated reduced expression of CD3-ζ in 10 of 11 preparations of T cells obtained from tumor-involved LNs. Similar reduction in expression of CD3-ζ was demonstrated by immunostaining performed in situ on frozen sections of melanoma tissues. Expression of p56(lck) and Zap-70, but not phospholipase C- γ1, was reduced in these patients' T cells relative to those obtained from normal individuals. In 50% of the patients, reduced expression of CD3-ζ and p56(lck) was observed in T lymphocytes obtained both from tumor-involved LNs and from peripheral blood. To determine whether deficient expression of these signaling molecules is reversible, T cells from melanoma-involved LNs were incubated in the presence of interleukin 2 (IL-2) for 48 h, and lysates from fresh or cultured lymphocytes were compared for changes in expression of signaling molecules. Cells cultured in the presence of IL-2 demonstrated increased expression of CD3-ζ and p56(lck), which approached the levels detected in normal T cells. However, the level of p56(lck) kinase activity did nut normalize in any of the LN-derived lymphocytes cultured in the presence of IL-2. Decreased expression of CD3-ζ or p56(lck) observed in the patients' T cells was not reversed by immunotherapy with IL-2 at low or high dose in those patients with metastatic melanoma who failed to respond to therapy. However, in three patients who achieved clinical responses, the initially reduced expression of ζ in peripheral blood T cells normalized following IL-2 therapy.

Original languageEnglish (US)
Pages (from-to)1263-1274
Number of pages12
JournalClinical Cancer Research
Volume2
Issue number8
StatePublished - Aug 1 1996
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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