title: Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine.
abstract: Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4+CD25hi regulatory T cells (Treg cells) have been described as an additional mechanism reducing immunity. We assessed 73 patients with B-cell chronic lymphocytic leukemia (CLL) and 42 healthy controls and demonstrated significantly increased frequencies of cytotoxic T lymphocyte-associated protein 4 (CTLA4+)-, Forkhead box P3 (FOXP3+)-, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+)-, CD62L+-, transforming growth factor beta1 (TGF-beta1+)-, interleukin 10 (IL-10+)-Treg cells in patients with CLL, with highest frequencies in untreated or progressing patients presenting with extended disease. Most surprisingly, in the majority of patients with CLL treated with fludarabine-containing therapy regimens the inhibitory function of Treg cells was decreased or even abrogated. In addition, frequencies of Treg cells were significantly decreased after therapy with fludarabine. In light of similar findings for cyclophosphamide the combination of fludarabine and cyclophosphamide might be further exploited in strategies reducing immunosuppression prior to cancer immunotherapy.
authors.affiliation: Molecular Tumor Biology and Tumor Immunology Clinic I for Internal Medicine, University of Cologne, Joseph-Stelzmann Str 9/Haus 16, 50931 Cologne, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.forename: Matthias
authors.initials: M
authors.lastname: Kochanek
authors.forename: Kamruz
authors.initials: K
authors.lastname: Darabi
authors.forename: Alexey
authors.initials: A
authors.lastname: Popov
authors.forename: Markus
authors.initials: M
authors.lastname: Jensen
authors.forename: Elmar
authors.initials: E
authors.lastname: Endl
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Michael
authors.initials: M
authors.lastname: von Bergwelt-Baildon
authors.forename: Svenja
authors.initials: S
authors.lastname: Debey
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D016753:Interleukin-10; D019041:L-Selectin; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology*; D008875:Middle Aged; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C508960:TGFB1 protein, human; C491405:TNFRSF18 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019041:L-Selectin; D016753:Interleukin-10; D014740:Vidarabine; C024352:fludarabine