Laboratory of Immunotherapy, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Int J Cancer. 2010 Sep 1;127(5):1141-50. doi: 10.1002/ijc.25140.
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.
白细胞介素 21（IL-21）是白细胞介素 2 细胞因子家族的成员，由 CD4+T 细胞产生。我们之前的研究表明，用转导白细胞介素 21 的神经母细胞瘤细胞（Neuro2a/IL-21）进行免疫治疗（IT）可以治愈 33%患有系统性神经母细胞瘤的同基因小鼠。在这里，我们研究了去除调节性 T 细胞（Treg 细胞）是否可以增强 Neuro2a/IL-21 疫苗的治疗效果。用靶向 Treg 细胞的抗 CD25 mAb 给药，稍微增强了疫苗 IT 的效果（治愈率为 50%），但抗 CD4 mAb 的效果更强，治愈率为 80%。抗 CD25 mAb 确实仅部分耗尽了 CD4+CD25+FoxP3+Treg 细胞，而抗 CD4 mAb 在这方面更有效，导致 90%的 Treg 细胞耗竭。在接受疫苗+抗 CD4 mAb 治疗的小鼠中，它们对神经母细胞瘤产生了系统性免疫，90 天内 CD4+T 细胞计数完全恢复。耗尽 CD8+T 细胞会消除联合 IT 的效果，表明这些细胞在驱动免疫反应中起主要作用。此外，从接受 Neuro2a/亲本细胞（pc）共注射的治愈小鼠中分离出的 CD8+T 细胞完全抑制了肿瘤的生长。从接受 Neuro2a/IL-21 疫苗接种的小鼠的脾脏细胞中观察到 IFN-α2、β1 和γmRNA 的表达增加。此外，单独接受疫苗治疗或疫苗+抗 CD4 mAb 治疗的小鼠的血清 IFN-γ水平增加，并且在脾脏细胞中发现了产生 IFN-γ的 CD8+T 细胞。总之，抗 CD4 mAb 通过去除 Treg 细胞及其前体和其他潜在的免疫抑制性 CD4+细胞亚群来增强基于白细胞介素 21 的 IT，从而允许开发由白细胞介素 21 驱动的 CD8+T 细胞反应，介导神经母细胞瘤的排斥。
