Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer

Hans J van der Vliet, Hans J J van der Vliet, Henry B Koon, Simon C Yue, Burak Uzunparmak, Virginia Seery, Marc A Gavin, Alexander Y Rudensky, Michael B Atkins, Steven P Balk, Mark A Exley

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PURPOSE: High-dose recombinant human interleukin-2 (IL-2) therapy is of clinical benefit in a subset of patients with advanced melanoma and renal cell cancer. Although IL-2 is well known as a T-cell growth factor, its potential in vivo effects on human immunoregulatory cell subsets are largely unexplored.

EXPERIMENTAL DESIGN: Here, we studied the effects of high-dose IL-2 therapy on circulating dendritic cell subsets (DC), CD1d-reactive invariant natural killer T cells (iNKT), and CD4(+)CD25(+) regulatory-type T cells.

RESULTS: The frequency of both circulating myeloid DC1 and plasmacytoid DC decreased during high-dose IL-2 treatment. Of these, only a significant fraction of myeloid DC expressed CD1d. Although the proportion of Th1-type CD4(-) iNKT increased, similarly to DC subsets, the total frequency of iNKT decreased during high-dose IL-2 treatment. In contrast, the frequency of CD4(+)CD25(+) T cells, including CD4(+)Foxp3(+) T cells, which have been reported to suppress antitumor immune responses, increased during high-dose IL-2 therapy. However, there was little, if any, change of expression of GITR, CD30, or CTLA-4 on CD4(+)CD25(+) T cells in response to IL-2. Functionally, patient CD25(+) T cells at their peak level (immediately after the first cycle of high-dose IL-2) were less suppressive than healthy donor CD25(+) T cells and mostly failed to Th2 polarize iNKT.

CONCLUSIONS: Our data show that there are reciprocal quantitative and qualitative alterations of immunoregulatory cell subsets with opposing functions during treatment with high-dose IL-2, some of which may compromise the establishment of effective antitumor immune responses.

Original languageEnglish
Pages (from-to)2100-8
Number of pages9
JournalClinical Cancer Research
Issue number7
Publication statusPublished - 1 Apr 2007


  • Adult
  • Aged
  • Carcinoma, Renal Cell/drug therapy
  • Dendritic Cells/drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Flow Cytometry
  • Humans
  • Interleukin-2 Receptor alpha Subunit/metabolism
  • Interleukin-2/therapeutic use
  • Kidney Neoplasms/drug therapy
  • Killer Cells, Natural/drug effects
  • Lymphocyte Subsets/drug effects
  • Male
  • Melanoma/drug therapy
  • Middle Aged
  • T-Lymphocytes, Regulatory/drug effects

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