title: Recombinant IL-21 and anti-CD4 antibodies cooperate in syngeneic neuroblastoma immunotherapy and mediate long-lasting immunity.
abstract: IL-21 is an immune-enhancing cytokine, which showed promising results in cancer immunotherapy. We previously observed that the administration of anti-CD4 cell-depleting antibody strongly enhanced the anti-tumor effects of an IL-21-engineered neuroblastoma (NB) cell vaccine. Here, we studied the therapeutic effects of a combination of recombinant (r) IL-21 and anti-CD4 monoclonal antibodies (mAb) in a syngeneic model of disseminated NB. Subcutaneous rIL-21 therapy at 0.5 or 1 μg/dose (at days 2, 6, 9, 13 and 15 after NB induction) had a limited effect on NB development. However, coadministration of rIL-21 at the two dose levels and a cell-depleting anti-CD4 mAb cured 28 and 70 % of mice, respectively. Combined immunotherapy was also effective if started 7 days after NB implant, resulting in a 30 % cure rate. Anti-CD4 antibody treatment efficiently depleted CD4(+) CD25(high) Treg cells, but alone had limited impact on NB. Combination immunotherapy by anti-CD4 mAb and rIL-21 induced a CD8(+) cytotoxic T lymphocyte response, which resulted in tumor eradication and long-lasting immunity. CD4(+) T cells, which re-populated mice after combination immunotherapy, were required for immunity to NB antigens as indicated by CD4(+) T cell depletion and re-challenge experiments. In conclusion, these data support a role for regulatory CD4(+) T cells in a syngeneic NB model and suggest that rIL-21 combined with CD4(+) T cell depletion reprograms CD4(+) T cells from immune regulatory to anti-tumor functions. These observations open new perspectives for the use of IL-21-based immunotherapy in conjunction with transient CD4(+) T cell depletion, in human metastatic NB.
authors.affiliation: IRCCS A.O.U. San Martino-IST, National Institute for Cancer Research, Largo R. Benzi 10, 16132, Genoa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Rigo
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: Corrias
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Orengo
authors.forename: Antonella
authors.initials: A
authors.lastname: Brizzolara
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.forename: Daniela
authors.initials: D
authors.lastname: Fenoglio
authors.forename: Gilberto
authors.initials: G
authors.lastname: Filaci
authors.forename: Michela
authors.initials: M
authors.lastname: Croce
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007167:Immunotherapy / Q000379:methods*; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D008212:Lymphocyte Depletion / Q000379:methods; D051379:Mice; D009447:Neuroblastoma / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D019496:Cancer Vaccines; D007378:Interleukins; D011994:Recombinant Proteins; D000098546:Interleukin-21