RNA interference targeting transforming growth factor-β enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo
RNA interference targeting transforming growth factor-β enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo
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DOI：
10.1158/0008-5472.can-04-1627
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发表时间：
2004-10-15
期刊：
影响因子：
11.2
通讯作者：
Weller, M
中科院分区：
文献类型：
--
作者：
Friese, MA;Wischhusen, J;Weller, M
转化生长因子（TGF）-β是与恶性胶质瘤患者免疫功能受损有关的关键分子。在这里，我们报告说，胶质母细胞瘤，最常见的和致命的类型的人类胶质瘤，患者表现出减少表达的活化免疫受体NKG 2D的CD 8（+）T和自然杀伤（NK）细胞。TGF-β在体外下调胶质瘤患者血清和脑脊液中CD 8（+）T和NK细胞NKG 2D表达。此外，TGF-β抑制NKG 2D配体云母的转录。通过小干扰RNA技术干扰TGF-β 1和TGF-β 2的合成，阻止了LNT-229胶质瘤细胞上清液介导的免疫细胞上NKG 2D的下调，并强烈增强了胶质瘤细胞中云母的表达，促进了CD 8（+）T和NK细胞对其的识别和裂解。此外，TGF-β沉默导致体外迁移性和侵袭性较低的胶质瘤细胞表型。TGF-β缺陷的LNT-229神经胶质瘤细胞在裸鼠中表现出皮下和原位致瘤性的丧失，并且从这些小鼠中分离的NK细胞显示出活化的表型。靶向TGF-β 1，2的RNA干扰导致胶质瘤细胞表型对免疫细胞裂解更敏感，体外运动性更低，在裸鼠中无致瘤性，强烈证实TGF-β拮抗作用是未来治疗恶性胶质瘤的主要治疗策略。
Transforming growth factor (TGF)-beta is the key molecule implicated in impaired immune function in human patients with malignant gliomas. Here we report that patients with glioblastoma, the most common and lethal type of human glioma, show decreased expression of the activating immumoreceptor NKG2D in CD8(+) T and natural killer (NK) cells. TGF-beta is responsible for the down-regulation of NKG2D expression in CD8(+) T and NK cells mediated by serum and cerebrospinal fluid of glioma patients in vitro. Moreover, TGF-beta inhibits the transcription of the NKG2D ligand MICA. Interference with the synthesis of TGF-beta1 and TGF-beta2 by small interfering RNA technology prevents the down-regulation of NKG2D on immune cells mediated by LNT-229 glioma cell supernatant and strongly enhances MICA expression in the glioma cells and promotes their recognition and lysis by CD8(+) T and NK cells. Furthermore, TGF-beta silencing results in a less migratory and invasive glioma cell phenotype in vitro. LNT-229 glioma cells deficient in TGF-beta exhibit a loss of subcutaneous and orthotopic tumorigenicity in nude mice, and NK cells isolated from these mice show an activated phenotype. RNA interference targeting TGF-beta1,2 results in a glioma cell phenotype that is more sensitive to immune cell lysis and less motile in vitro and nontumorigenic in nude mice, strongly confirming TGF-beta antagonism as a major therapeutic strategy for the future treatment of malignant gliomas.