Recombinant IL-21 and anti-CD4 antibodies cooperate in syngeneic neuroblastoma immunotherapy and mediate long-lasting immunity

Valentina Rigo, Maria Valeria Corrias, Anna Maria Orengo, Antonella Brizzolara, Laura Emionite, Daniela Fenoglio, Gilberto Filaci, Michela Croce, Silvano Ferrini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)501-511
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume63
Issue number5
DOIs
Publication statusPublished - 2014

Fingerprint

Neuroblastoma
Immunotherapy
Anti-Idiotypic Antibodies
Immunity
Regulatory T-Lymphocytes
T-Lymphocytes
Monoclonal Antibodies
Neoplasms
interleukin-21
Cytotoxic T-Lymphocytes
Therapeutic Uses
Vaccines
Cytokines
Antigens
Antibodies
Therapeutics

Keywords

  • IL-21
  • Immunotherapy
  • Monoclonal antibody
  • Neuroblastoma
  • T cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

Cite this

Recombinant IL-21 and anti-CD4 antibodies cooperate in syngeneic neuroblastoma immunotherapy and mediate long-lasting immunity. / Rigo, Valentina; Corrias, Maria Valeria; Orengo, Anna Maria; Brizzolara, Antonella; Emionite, Laura; Fenoglio, Daniela; Filaci, Gilberto; Croce, Michela; Ferrini, Silvano.

In: Cancer Immunology, Immunotherapy, Vol. 63, No. 5, 2014, p. 501-511.

Research output: Contribution to journalArticle

Rigo, Valentina ; Corrias, Maria Valeria ; Orengo, Anna Maria ; Brizzolara, Antonella ; Emionite, Laura ; Fenoglio, Daniela ; Filaci, Gilberto ; Croce, Michela ; Ferrini, Silvano. / Recombinant IL-21 and anti-CD4 antibodies cooperate in syngeneic neuroblastoma immunotherapy and mediate long-lasting immunity. In: Cancer Immunology, Immunotherapy. 2014 ; Vol. 63, No. 5. pp. 501-511.
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AU - Rigo, Valentina

AU - Corrias, Maria Valeria

AU - Orengo, Anna Maria

AU - Brizzolara, Antonella

AU - Emionite, Laura

AU - Fenoglio, Daniela

AU - Filaci, Gilberto

AU - Croce, Michela

AU - Ferrini, Silvano

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AB - 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.

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