Details

Autor(en) / Beteiligte

• 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

Titel

EZH2 Inhibition in Ewing Sarcoma Upregulates GD2 Expression for Targeting with Gene-Modified T Cells

Ist Teil von

• Molecular therapy, 2019-05, Vol.27 (5), p.933-946

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2019

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. Kailayangiri et al. report that small-molecule inhibitors of EZH2 methyltransferase activity reliably upregulate the ganglioside GD2 on the surface of Ewing sarcoma cells and render GD2-negative tumor cells susceptible to targeting with GD2-specific CAR T cells.