Fenretinide sensitizes multidrug-resistant human neuroblastoma cells to antibody-independent and ch14.18-mediated NK cell cytotoxicity.
Fenretinide sensitizes multidrug-resistant human neuroblastoma cells to antibody-independent and ch14.18-mediated NK cell cytotoxicity.
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Fenretinide 使多重耐药人神经母细胞瘤细胞对不依赖抗体且 ch14.18 介导的 NK 细胞毒性敏感。
DOI：
10.1007/s00109-012-0958-0
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Huebener,Nicole
中科院分区：
文献类型：
--
作者：
Shibina,Anastasia;Seidel,Diana;Somanchi,SrinivasS;Lee,DeanA;Stermann,Alexander;Maurer,BarryJ;Lode,HolgerN;Reynolds,CPatrick;Huebener,Nicole
神经母细胞瘤(NB)是儿童最常见的颅外实体瘤。被动免疫治疗联合抗二唾液酸神经节苷脂GD2抗体(ch14.18/sp2/0)和细胞因子与13-顺式维甲酸联合清髓后维持治疗可提高高危神经母细胞瘤的存活率，但这些儿童的总体预后仍需改善。芬维甲素(4-HPR)是一种人工合成的维甲酸，在复发性NB中表现出临床活性，对多种癌细胞具有细胞毒性，部分是通过GD2的前体二氢神经酰胺的积累。我们研究了4-HPR对CHO来源、CH14.18介导的抗NB效应功能、补体依赖的细胞毒作用(CDC)以及抗体依赖和抗体非依赖性细胞毒作用(ADCC和AICC)的影响。在这里，我们首次证明了用4-HPR预处理非维甲酸耐药的NB细胞显著增强了CH14.18/CHO介导的CDC、ADCC和AICC由人自然杀伤细胞和外周血单核细胞共同作用。4-HPR可增加耐药细胞GD2和死亡受体(DR)的表达，并诱导效应细胞产生颗粒酶B和穿孔素。用葡萄糖神经酰胺合成酶抑制剂阻断神经节苷脂的合成可抑制ADCC反应的增强，但对AICC无影响，表明4-HPR诱导的GD2介导了NB细胞对ADCC的增敏作用。我们还发现，4-HPR诱导了耐药NB异种移植模型中GD2和DR的表达增加，这与使用4-HPR处理的小鼠移植的肿瘤靶细胞的ADCC和AICC反应增加有关。综上所述，这些发现为4-HPR和被动免疫疗法与ch14.18/cho在未来针对高危NB患者的临床试验中的结合提供了重要的基线。
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Combining passive immunotherapy with an antibody to the disialoganglioside GD2 (ch14.18/SP2/0) and cytokines with 13-cis-retinoic acid for post-myeloablative maintenance therapy increased survival in high-risk NB, but the overall prognosis for these children is still in need of improvement. Fenretinide (4-HPR) is a synthetic retinoid that has shown clinical activity in recurrent NB and is cytotoxic to a variety of cancer cells, in part via the accumulation of dihydroceramides, which are precursors of GD2. We investigated the effect of 4-HPR on CHO-derived, ch14.18-mediated anti-NB effector functions, complement-dependent cytotoxicity (CDC), and antibody-dependent and antibody-independent cellular cytotoxicity (ADCC and AICC, respectively). Here, we demonstrate for the first time that pretreatment of fenretinide-resistant NB cells with 4-HPR significantly enhanced ch14.18/CHO-mediated CDC and ADCC and AICC by both human natural killer cells and peripheral blood mononuclear cells. Treatment with 4-HPR increased GD2 and death receptor (DR) expression in resistant NB cells and induced an enhanced granzyme B and perforin production by effector cells. Blocking of ganglioside synthesis with a glucosylceramide synthase inhibitor abrogated the increased ADCC response but had no effect on the AICC, indicating that GD2 induced by 4-HPR mediates the sensitization of NB cells for ADCC. We also showed that 4-HPR induced increased GD2 and DR expression in a resistant NB xenograft model that was associated with an increased ADCC and AICC response using explanted tumor target cells from 4-HPR-treated mice. In summary, these findings provide an important baseline for the combination of 4-HPR and passive immunotherapy with ch14.18/CHO in future clinical trials for high-risk NB patients.
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DOI：
10.1093/geronj/43.4.m101
发表时间：
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