Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine

Abstract

IMMUNOBIOLOGY Reduced frequencies and suppressive function of CD4
CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine Marc Beyer, Matthias Kochanek, Kamruz Darabi, Alexey Popov, Markus Jensen, Elmar Endl, Percy A. Knolle, Roman K. Thomas, Michael von Bergwelt-Baildon, Svenja Debey, Michael Hallek, and Joachim L. Schultze Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the devel- opment of clinically efficient cancer immu- notherapy. Inhibition of antitumor im- mune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased fre- quencies of CD4
CD25hi regulatory T cells (Treg cells) have been described as an additional mechanism reducing immu- nity. We assessed 73 patients with B-cell chronic lymphocytic leukemia (CLL) and 42 healthy controls and demonstrated significantly increased frequencies of cy- totoxic T lymphocyte-associated protein 4 (CTLA4
)–, Forkhead box P3 (FOXP3
)–, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR
)–, CD62L
–, transforming growth factor 1 (TGF-1
)–, interleukin 10 (IL-10
)–Treg cells in patients with CLL, with highest frequencies in untreated or progressing patients presenting with extended dis- ease. Most surprisingly, in the majority of patients with CLL treated with fludarabine- containing therapy regimens the inhibi- tory function of Treg cells was decreased or even abrogated. In addition, frequen- cies of Treg cells were significantly de- creased after therapy with fludarabine. In light of similar findings for cyclophospha- mide the combination of fludarabine and cyclophosphamide might be further ex- ploited in strategies reducing immunosup- pression prior to cancer immunotherapy. (Blood. 2005;106:2018-2025) © 2005 by The American Society of Hematology Introduction Human and murine CD4
CD25
T cells contain cells that suppress antigen-specific T-cell imm