title: Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Cancer Biology Program, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: van der Vliet
authors.forename: Hans J J
authors.initials: HJ
authors.lastname: van der Vliet
authors.forename: Henry B
authors.initials: HB
authors.lastname: Koon
authors.forename: Simon C
authors.initials: SC
authors.lastname: Yue
authors.forename: Burak
authors.initials: B
authors.lastname: Uzunparmak
authors.forename: Virginia
authors.initials: V
authors.lastname: Seery
authors.forename: Marc A
authors.initials: MA
authors.lastname: Gavin
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.forename: Mark A
authors.initials: MA
authors.lastname: Exley
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit