title: In vivo expansion of naïve CD4+ CD25(high) FOXP3+ regulatory T cells in patients with colorectal carcinoma after IL-2 administration.
abstract: Regulatory T cells (T(reg) cells) are increased in context of malignancies and their expansion can be correlated with higher disease burden and decreased survival. Initially, interleukin 2 (IL-2) has been used as T-cell growth factor in clinical vaccination trials. In murine models, however, a role of IL-2 in development, differentiation, homeostasis, and function of T(reg) cells was established. In IL-2 treated cancer patients a further T(reg)-cell expansion was described, yet, the mechanism of expansion is still elusive. Here we report that functional T(reg) cells of a naïve phenotype--as determined by CCR7 and CD45RA expression--are significantly expanded in colorectal cancer patients. Treatment of 15 UICC stage IV colorectal cancer patients with IL-2 in a phase I/II peptide vaccination trial further enlarges the already increased naïve T(reg)-cell pool. Higher frequencies of T-cell receptor excision circles in naïve T(reg) cells indicate IL-2 dependent thymic generation of naïve T(reg) cells as a mechanism leading to increased frequencies of T(reg) cells post IL-2 treatment in cancer patients. This finding could be confirmed in naïve murine T(reg) cells after IL-2 administration. These results point to a more complex regulation of T(reg) cells in context of IL-2 administration. Future strategies therefore might aim at combining IL-2 therapy with novel strategies to circumvent expansion and differentiation of naïve T(reg) cells.
authors.affiliation: Life and Medical Sciences Institute, Genomics and Immunoregulation, University of Bonn, Bonn, Germany. marc.beyer@uni-bonn.de
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.forename: Beatrix
authors.initials: B
authors.lastname: Schumak
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weihrauch
authors.forename: Bettina
authors.initials: B
authors.lastname: Andres
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Elmar
authors.initials: E
authors.lastname: Endl
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.forename: Sabine
authors.initials: S
authors.lastname: Classen
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C491405:TNFRSF18 protein, human