title: CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine.
abstract: IL-21 is an IL-2-like cytokine, signaling through a specific IL-21R and the IL-2R gamma-chain. Because the TS/A mammary adenocarcinoma cells genetically modified to secrete IL-21 (TS/A-IL-21) are strongly immunogenic in syngeneic mice, we analyzed their application as vaccine. In mice bearing TS/A-parental cell (pc) micrometastases, vaccination with irradiated TS/A-IL-21 cells significantly increased the animal life span, but cured only 17% of mice. Spleen cells from cured mice developed CTL activity and produced IFN-gamma in response to stimulation by the AH1 epitope of the gp70env Ag of TS/A-pc. We tested whether the low therapeutic outcome might be due to CD4+CD25+ regulatory T cells (Treg) present in TS/A-pc tumors and draining lymph nodes and whether IL-21 had any effect on these cells. Indeed, CD4+CD25+ cells suppressed IFN-gamma production by splenocytes from immune mice in response to stimulation by the AH1 peptide. Low concentrations of IL-21 (10 ng/ml) failed to reverse the inhibitory activity of CD4+CD25+ cells in an allogeneic MLR, whereas 60 ng/ml rIL-21 partially restored responder T cell proliferation. IL-21R expression on CD25- lymphocytes suggested that IL-21 could be more effective in mice depleted of CD25+ cells. Depletion of Treg cells by a single dose of anti-CD25 mAb combined with TS/A-IL-21 cell vaccine cured >70% of mice bearing micrometastases, whereas anti-CD25 mAb treatment alone had no effect. Successful combined immunotherapy required NK cells, CD8+ T cells, and IFN-gamma. In conclusion, immunotherapy of micrometastases by an IL-21-based cellular vaccine is strongly potentiated by CD25+ cell depletion.
authors.affiliation: Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Comes
authors.forename: Ombretta
authors.initials: O
authors.lastname: Rosso
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Orengo
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
authors.forename: Carlo
authors.initials: C
authors.lastname: Sorrentino
authors.forename: Raffaella
authors.initials: R
authors.lastname: Meazza
authors.forename: Tiziana
authors.initials: T
authors.lastname: Piazza
authors.forename: Barbara
authors.initials: B
authors.lastname: Valzasina
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nanni
authors.forename: Mario P
authors.initials: MP
authors.lastname: Colombo
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
mesh_terms: D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000276:immunology / Q000517:prevention & control*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D007378:Interleukins; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; D000098546:Interleukin-21