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标题:Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma.
时间:2020-01-15 10:07:31
DOI:10.1038/s41598-017-14417-6
PMID:29070883
作者:Rigo, Valentina; Emionite, Laura; Daga, Antonio
出版源: 《Scientific Reports》 ,7 (1) :14049
摘要: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+CD25+Treg cells and other CD4+CD25−regulatory subsets. Here we show that mono-therapy with anti-PD-1/PD-L1 mAbs had no effect on systemic NB progressionin 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+T cell-related immune-regulatory mechanisms must be simultaneously blocked to mediate therapeutic effects in these models.
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目录:
  • Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma
    • Results
      • Anti-PD-1/PD-L1 mAb alone or their combinations with rIL-21 have no impact on the progression of PD-L1-expressing NB in syn ...
      • Combination therapy with anti-PD-1/PD-L1 plus anti-CD4 mAb showed synergistic activity and cured mice from disseminated NB. ...
      • Delayed combined immunotherapy is effective.
      • Combination and delayed combined therapy with anti-PD-1 plus anti-CD4 mAb showed synergistic activity also in NXS2 dissemin ...
      • Mechanisms involved in anti-tumor responses induced by anti-PD-1/anti-CD4 combination immunotherapy.
    • Discussion
    • Materials and Methods
      • Cell cultures and IFN-γ treatment.
      • Animal models and treatments.
      • Analysis by In Vivo Imaging Systems (IVIS).
      • RNA and RT-PCR analysis.
      • Immunofluorescence and FACS analysis.
      • In vitro re-stimulation and cytotoxicity.
      • IFN-γ ELISA in co-culture supernatant.
      • Immunohistochemistry analysis.
      • Statistical analyses.
    • Acknowledgements
    • Figure 1 Neuro2a cells express PD-L1 but anti-PD-1 or anti-PD-L1 blocking mAbs have no impact on Neuro2a tumor progression in syngeneic mice.
    • Figure 2 The combination of anti-PD-1 or anti-PD-L1 with a cell-depleting anti-CD4 mAb inhibits NB progression.
    • Figure 3 Delayed combination therapy with anti-PD-1 and anti-CD4 mAb is effective and leads to a long-lasting immunity to NB.
    • Figure 4 Combination therapy with anti-PD-1 and anti-CD4 mAb significantly prolong NXS2-tumor-free progression in mice.
    • Figure 5 Spleen cells from mice cured by combination therapy with anti-PD-1 and anti-CD4 mAb display CTL responses in vitro.
    • Figure 6 CD8+ T cells are the main effector cells involved in combination therapy with anti-PD-1 and anti-CD4 mAb.

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