RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo.
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RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. / Friese, Manuel A.; Wischhusen, Jörg; Wick, Wolfgang; Weiler, Markus; Eisele, Günter; Steinle, Alexander; Weller, Michael.
in: CANCER RES, Jahrgang 64, Nr. 20, 20, 2004, S. 7596-7603.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo.
AU - Friese, Manuel A.
AU - Wischhusen, Jörg
AU - Wick, Wolfgang
AU - Weiler, Markus
AU - Eisele, Günter
AU - Steinle, Alexander
AU - Weller, Michael
PY - 2004
Y1 - 2004
N2 - 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 immunoreceptor 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.
AB - 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 immunoreceptor 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 64
SP - 7596
EP - 7603
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 20
M1 - 20
ER -