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RNA Interference Targeting Transforming Growth Factor-ß Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity In vivo

¹ Department of General Neurology, Hertie Institute for Clinical Brain Research and ² Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany

Transforming growth factor (TGF)-ß 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 immunoreceptor NKG2D in CD8⁺ T and natural killer (NK) cells. TGF-ß 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-ß inhibits the transcription of the NKG2D ligand MICA. Interference with the synthesis of TGF-ß1 and TGF-ß2 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-ß silencing results in a less migratory and invasive glioma cell phenotype in vitro. LNT-229 glioma cells deficient in TGF-ß 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-ß1,2 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-ß antagonism as a major therapeutic strategy for the future treatment of malignant gliomas.

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