Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors
Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors
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DOI：
10.1038/nm.2366
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发表时间：
2011-06-01
期刊：
影响因子：
82.9
通讯作者：
Zitvogel, Laurence
中科院分区：
文献类型：
--
作者：
Delahaye, Nicolas F.;Rusakiewicz, Sylvie;Zitvogel, Laurence
自然杀伤 (NK) 细胞受体 NKp30 参与肿瘤和树突状细胞 (DC) 的识别。在这里，我们描述了三种 NKp30 剪接变体对胃肠道肉瘤 (GIST) 预后的影响，GIST 是一种表达 NKp30 配体的恶性肿瘤，并用 NK 刺激性 KIT 酪氨酸激酶抑制剂治疗。健康个体和 GIST 患者表现出功能不同的 NKp30 亚型的不同转录模式。在对 80 名 GIST 患者进行的回顾性分析中，免疫抑制性 NKp30c 亚型（相对于免疫刺激性 NKp30a 和 NKp30b 亚型）的主要表达与受试者生存率降低、NKp30 依赖性肿瘤坏死因子-α (TNF-α) 和 CD107a 释放减少以及干扰素-γ (IFN-γ) 和白介素-12 缺陷相关NK-DC 串扰中的 (IL-12) 分泌可通过阻断 IL-10 来恢复。 NKp30c 的优先表达部分是由于编码 NKp30 的基因 3' 非翻译区 3790 位的单核苷酸多态性所致。基因决定的 NKp30 状态可预测 GIST 个体的临床结果，与 KIT 突变无关。
The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-alpha (TNF-alpha) and CD107a release, and defective interferon-gamma (IFN-gamma) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.