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Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma.
- Source :
-
Scientific reports [Sci Rep] 2017 Oct 25; Vol. 7 (1), pp. 14049. Date of Electronic Publication: 2017 Oct 25. - Publication Year :
- 2017
-
Abstract
- Anti-PD-1 or anti-PD-L1 blocking monoclonal antibodies (mAbs) have shown potent anti-tumor effects in adult cancer patients and clinical studies have recently been started in pediatric cancers, including high-risk/relapsing neuroblastoma (NB). Therefore, we studied the effects of anti-PD-1/PD-L1 mAbs in two syngeneic models of disseminated NB generated by the injection of either Neuro2a or NXS2 cells, which express PD-L1. In addition, we tested the combination of these agents with the immune-enhancing cytokine IL-21, the Ecto-NTPDase inhibitor POM-1, an anti-CD25 mAb targeting Treg cells, or an anti-CD4 mAb. We previously showed that CD4-transient depletion removes CD4 <superscript>+</superscript> CD25 <superscript>+</superscript> Treg cells and other CD4 <superscript>+</superscript> CD25 <superscript>-</superscript> regulatory subsets. Here we show that mono-therapy with anti-PD-1/PD-L1 mAbs had no effect on systemic NB progression in vivo, and also their combination with IL-21, POM-1 or anti-CD25 mAb was ineffective. The combined use of anti-PD-1 with an anti-CD4 mAb mediated a very potent, CD8-dependent, synergistic effect leading to significant elongation of tumor-free survival of mice, complete tumor regression and durable anti-NB immunity. Similar results were obtained by combining the anti-PD-L1 and anti-CD4 mAbs. These findings indicate that both PD-1/PD-L1 and CD4 <superscript>+</superscript> T cell-related immune-regulatory mechanisms must be simultaneously blocked to mediate therapeutic effects in these models.
- Subjects :
- Animals
Apoptosis
Cell Proliferation
Female
Immunologic Factors
Interleukins immunology
Lymphocyte Depletion
Mice
Mice, Inbred A
Neuroblastoma immunology
Neuroblastoma metabolism
Neuroblastoma pathology
T-Lymphocytes, Regulatory drug effects
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory pathology
Tumor Cells, Cultured
Antibodies, Monoclonal therapeutic use
B7-H1 Antigen immunology
CD4 Antigens immunology
Cytotoxicity, Immunologic immunology
Immunotherapy
Neuroblastoma therapy
Programmed Cell Death 1 Receptor immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29070883
- Full Text :
- https://doi.org/10.1038/s41598-017-14417-6