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: Michela Croce, Maria Valeria Corrias, Anna Maria Orengo, Antonella Brizzolara, Barbara Carlini, Martina Borghi, Valentina Rigo, Vito Pistoia, Silvano Ferrini
• Journal: International journal of cancer (Int J Cancer) Vol. 127 Issue 5 Pg. 1141-50 (Sep 01 2010) ISSN: 1097-0215 [Electronic] United States
• PMID: 20039320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Cancer Vaccines
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-2 Receptor alpha Subunit
• Interleukins
• Membrane Proteins
• RNA, Messenger
• Transforming Growth Factor beta
• Interleukin-10
• Interferon-gamma
• Ptgs2 protein, mouse
• Cyclooxygenase 1
• Cyclooxygenase 2
• Ptgs1 protein, mouse
• interleukin-21

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Blotting, Western
• CD4-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (therapeutic use)
• Cyclooxygenase 1 (genetics)
• Cyclooxygenase 2 (genetics)
• Female
• Flow Cytometry
• Fluorescent Antibody Technique
• Forkhead Transcription Factors (metabolism)
• Immunotherapy
• Interferon-gamma (metabolism)
• Interleukin-10 (genetics)
• Interleukin-2 Receptor alpha Subunit (immunology)
• Interleukins (therapeutic use)
• Lymphocyte Depletion
• Membrane Proteins (genetics)
• Mice
• Mice, Inbred A
• Mice, Inbred NOD
• Mice, SCID
• Neuroblastoma (immunology, pathology, therapy)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Transforming Growth Factor beta (genetics)