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Effects of the Administration of High-Dose Interleukin-2 on Immunoregulatory Cell Subsets in Patients with Advanced Melanoma and Renal Cell Cancer

Authors' Affiliations: ¹ Cancer Biology Program, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; ² Department of Internal Medicine, Vrije Universiteit Medisch Centrum, Amsterdam, the Netherlands; and ³ Department of Immunology, University of Washington, Seattle, Washington

Requests for reprints: Mark A. Exley, Harvard Institutes of Medicine, 330 Brookline Avenue, Boston, MA 02115. Phone: 617-667-0982; E-mail: mexley{at}bidmc.harvard.edu.

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.

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