High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells
High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells
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DOI：
10.1158/0008-5472.can-04-0757
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发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Borrello, I
中科院分区：
文献类型：
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作者：
Serafini, P;Carbley, R;Borrello, I
肿瘤疫苗在早期临床试验中显示出了希望。其中，基因工程肿瘤细胞能分泌具有生物活性的粒细胞-巨噬细胞集落刺激因子(GM-CSF)，可产生全身性抗肿瘤免疫反应。尽管由修饰的肿瘤细胞产生的达到可测量的抗肿瘤效果所需的最小GM-CSF剂量是众所周知的，但没有数据检验这种疫苗接种策略是否存在治疗上限。由于最近的数据显示了肿瘤生长产生的GM-CSF的免疫抑制作用，因此我们试图确定在疫苗配方中使用高剂量的GM-CSF是否会损害抗肿瘤免疫。使用一种疫苗策略，将产生GM-CSF的旁观者细胞系(B78H1-GM)与自体肿瘤混合在一起，我们评估了不同剂量的GM-CSF在保持恒定抗原剂量的情况下的影响。我们的结果定义了一个阈值，超过这个阈值，基于GM-CSF的疫苗不仅失去效力，更重要的是它的临床意义导致了体内实质性的免疫抑制。超过这一阈值，GM-CSF诱导的Gr1(+)/CD11b(+)髓系抑制细胞显著削弱抗原特异性T细胞反应，并对体内抗肿瘤免疫反应产生不利影响。GM-CSF的双重作用是由这种细胞因子的全身浓度而不是局部浓度介导的。髓系抑制细胞诱导的免疫抑制是通过诱导型一氧化氮合酶产生一氧化氮来实现的，因为诱导型一氧化氮合酶抑制剂L可以在体外恢复抗原特异性T细胞的反应性。综上所述，我们的数据显示了GMCSF超治疗疫苗剂量的负面影响，并强调了识别这些关键变量的重要性，以努力提高肿瘤疫苗的治疗效果。
Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by modified tumor cells to achieve a measurable antitumor effect is well known, no data examined whether an upper therapeutic limit may exist for this vaccination strategy. Because recent data demonstrate an immunosuppressive effect of GM-CSF produced by growing tumors, we thus sought to determine whether high GM-CSF doses administered in a vaccine formulation could impair antitumor immunity. Using a vaccine strategy involving a GM-CSF-producing bystander cell line (B78H1-GM) admixed with autologous tumor, we assessed the impact of varying doses of GM-CSF while maintaining a constant antigen dose. Our results defined a threshold above which a GM-CSF-based vaccine not only lost its efficacy, but more importantly for its clinical implications resulted in substantial immunosuppression in vivo. Above this threshold, GM-CSF induced Gr1(+)/CD11b(+) myeloid suppressor cells that substantially impaired antigen-specific T-cell responses and adversely affected antitumor immune responses in vivo. The dual effects of GM-CSF are mediated by the systemic and not local concentration of this cytokine. Myeloid suppressor cell-induced immunosuppression is mediated by nitric oxide production via inducible nitric oxide synthase (iNOS) because the specific iNOS inhibitor, L-NMMA, restored antigen-specific T-cell responsiveness in vitro. Taken together, our data demonstrated the negative impact of supra-therapeutic vaccine doses of GMCSF and underscored the importance of identifying these critical variables in an effort to increase the therapeutic efficacy of tumor vaccines.