title: Transient depletion of CD4(+) T cells augments IL-21-based immunotherapy of disseminated neuroblastoma in syngeneic mice.
abstract: IL-21 is a member of the IL-2 cytokine family, produced by CD4+ T cells. We previously showed that immunotherapy (IT) with IL-21-transduced neuroblastoma cells (Neuro2a/IL-21) cured 33% of syngeneic mice bearing systemic NB. Here, we studied whether the removal of Treg cells could potentiate the therapeutic efficacy of Neuro2a/IL-21 vaccine. The administration of anti-CD25 mAb, which targets Treg cells, slightly potentiated the effect of vaccine IT (50% cure rate), but anti-CD4 mAb had a more potent effect leading to 80% cure rate. Anti-CD25 mAb, indeed, only partially depleted CD4+CD25+FoxP3+ Treg cells, whereas anti-CD4 mAb was more effective in this respect, leading to 90% depletion of Treg cells. In mice receiving vaccine+anti-CD4 mAb, which developed systemic immunity to NB, CD4+ T cells counts completely recovered in 90 days. Depletion of CD8+ T cells abrogated the effect of the combined IT, indicating a predominant role of these cells in driving the immune response. In addition, CD8+ T cells from cured mice coinjected with Neuro2a/parental cells (pc) in NOD-SCID mice completely inhibited tumor growth. Spleen cells from mice receiving Neuro2a/IL-21 vaccination showed increased expression of IFN-alpha2, -beta1 and -gamma mRNA. Moreover, mice receiving vaccine therapy alone or vaccine+anti-CD4 mAb showed increased IFN-gamma serum levels and IFN-gamma-producing CD8+ T cells were found in spleen cells. In conclusion, anti-CD4 mAb potentiated IL-21-based IT by removing Treg cells and/or their precursors and other potentially immune-suppressive CD4+ cell subsets, thus allowing the development of an IL-21-driven CD8+ T cell response, which mediates NB rejection.
authors.affiliation: Laboratory of Immunotherapy, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Croce
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: Barbara
authors.initials: B
authors.lastname: Carlini
authors.forename: Martina
authors.initials: M
authors.lastname: Borghi
authors.forename: Valentina
authors.initials: V
authors.lastname: Rigo
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007378:Interleukins / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008805:Mice, Inbred A; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics; D000098546:Interleukin-21
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D008565:Membrane Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D000098546:Interleukin-21