Transient depletion of CD4+ T cells augments IL-21-based immunotherapy of disseminated neuroblastoma in syngeneic mice
Transient depletion of CD4+ T cells augments IL-21-based immunotherapy of disseminated neuroblastoma in syngeneic mice
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DOI：
10.1002/ijc.25140
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发表时间：
2010-09-01
影响因子：
6.4
通讯作者：
Ferrini, Silvano
中科院分区：
文献类型：
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作者：
Croce, Michela;Corrias, Maria Valeria;Ferrini, Silvano
IL-21是IL-2细胞因子家族的成员，由CD 4 + T细胞产生。我们先前表明，IL-21转导的神经母细胞瘤细胞（Neuro 2a/IL-21）的免疫治疗（IT）治愈了33%的携带全身性NB的同基因小鼠。在这里，我们研究了Treg细胞的去除是否可以增强Neuro 2a/IL-21疫苗的治疗效果。靶向Treg细胞的抗CD 25 mAb的施用略微增强了疫苗IT的效果（50%治愈率），但抗CD 4 mAb具有更强效的效果，导致80%治愈率。实际上，抗-CD 25 mAb仅部分耗尽CD 4 + CD 25 + FoxP 3 + Treg细胞，而抗-CD 4 mAb在这方面更有效，导致Treg细胞的90%耗尽。在接受疫苗+抗CD 4 mAb的小鼠中，其对NB产生全身免疫，CD 4 + T细胞计数在90天内完全恢复。CD 8 + T细胞的消耗消除了组合IT的作用，表明这些细胞在驱动免疫应答中的主导作用。此外，在NOD-SCID小鼠中，来自治愈小鼠的CD 8 + T细胞与Neuro 2a/亲本细胞（pc）共注射完全抑制肿瘤生长。来自接受Neuro 2a/IL-21疫苗接种的小鼠的脾细胞显示IFN-α 2、IFN-β 1和IFN-γ mRNA的表达增加。此外，接受单独疫苗治疗或疫苗+抗CD 4 mAb的小鼠显示IFN-γ血清水平升高，并且在脾细胞中发现产生IFN-γ的CD 8 + T细胞。总之，抗CD 4 mAb通过去除Treg细胞和/或其前体和其他潜在的免疫抑制性CD 4+细胞亚群来增强基于IL-21的IT，从而允许产生IL-21驱动的CD 8 + T细胞应答，其介导NB排斥。
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.