EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells
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EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells. / Kailayangiri, Sareetha; Altvater, Bianca; Lesch, Stefanie; Balbach, Sebastian; Göttlich, Claudia; Kühnemundt, Johanna; Mikesch, Jan-Henrik; Schelhaas, Sonja; Jamitzky, Silke; Meltzer, Jutta; Farwick, Nicole; Greune, Lea; Fluegge, Maike; Kerl, Kornelius; Lode, Holger N; Siebert, Nikolai; Müller, Ingo; Walles, Heike; Hartmann, Wolfgang; Rossig, Claudia.
In: MOL THER, Vol. 27, No. 5, 08.05.2019, p. 933-946.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - EZH2 Inhibition in Ewing Sarcoma Upregulates G Expression for Targeting with Gene-Modified T Cells
AU - Kailayangiri, Sareetha
AU - Altvater, Bianca
AU - Lesch, Stefanie
AU - Balbach, Sebastian
AU - Göttlich, Claudia
AU - Kühnemundt, Johanna
AU - Mikesch, Jan-Henrik
AU - Schelhaas, Sonja
AU - Jamitzky, Silke
AU - Meltzer, Jutta
AU - Farwick, Nicole
AU - Greune, Lea
AU - Fluegge, Maike
AU - Kerl, Kornelius
AU - Lode, Holger N
AU - Siebert, Nikolai
AU - Müller, Ingo
AU - Walles, Heike
AU - Hartmann, Wolfgang
AU - Rossig, Claudia
N1 - Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
PY - 2019/5/8
Y1 - 2019/5/8
N2 - Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.
AB - Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.
KW - Journal Article
U2 - 10.1016/j.ymthe.2019.02.014
DO - 10.1016/j.ymthe.2019.02.014
M3 - SCORING: Journal article
C2 - 30879952
VL - 27
SP - 933
EP - 946
JO - MOL THER
JF - MOL THER
SN - 1525-0016
IS - 5
ER -