2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells.
2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells.
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DOI：
10.1158/1078-0432.ccr-08-2810
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发表时间：
2009-08-01
期刊：
影响因子：
--
通讯作者：
Rossig C
中科院分区：
文献类型：
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作者：
Altvater B;Landmeier S;Pscherer S;Temme J;Schweer K;Kailayangiri S;Campana D;Juergens H;Pule M;Rossig C
癌症免疫治疗中新型自然杀伤 (NK) 细胞导向策略旨在特异性调节 NK 细胞受体信号与肿瘤特异性激活之间的平衡。信号淋巴细胞激活分子（SLAM）相关受体2B4（CD244）是NK细胞激活的重要调节因子。我们研究了 2B4 增强的激活信号是否可以将人类 NK 细胞的细胞溶解功能重定向到 NK 细胞耐药性和自体白血病和肿瘤靶点。来自健康供体和儿童白血病患者的体外刺激的 NK 细胞被 CD19 或 GD2 特异性嵌合受体 (CAR) 进行基因修饰，其中单独或组合含有 T 细胞受体 ζ 或 2B4 胞内结构域。单独的嵌合 2B4 信号传导无法诱导 IL-2 受体上调和细胞因子分泌，但触发了特异性脱颗粒反应。将2B4胞内结构域整合到TCR z CAR中，显着增强了NK细胞对表达抗原的白血病或神经母细胞瘤细胞的激活反应的各个方面，包括CD25上调、IFN-γ和TNF-α的分泌、溶细胞颗粒的释放和生长抑制，并在保持抗原的同时克服了自体白血病细胞的NK细胞抵抗 特异性。这些数据表明 2B4 受体在 NK 细胞中具有有效的共刺激作用。表达抗原特异性 2B4-ze 的 NK 细胞可能是白血病和其他恶性肿瘤过继免疫治疗的强大新工具。
Novel natural killer (NK) cell-directed strategies in cancer immunotherapy aim at specifically modulating the balance between NK cell receptor signals towards tumor-specific activation. The signaling lymphocyte activation molecule (SLAM)-related receptor 2B4 (CD244) is an important regulator of NK cell activation. We investigated whether 2B4-enhanced activation signals can redirect the cytolytic function of human NK cells to NK-cell resistant and autologous leukemia and tumor targets. In vitro stimulated NK cells from healthy donors and pediatric leukemia patients were gene-modified with CD19 or GD2-specific chimeric receptors (CARs) containing either the T cell receptor ζ or 2B4 endodomain alone or combined. Chimeric 2B4 signaling alone failed to induce IL-2 receptor upregulation and cytokine secretion but triggered a specific degranulation response. Integration of the 2B4 endodomain into TCRζ CARs significantly enhanced all aspects of the NK-cell activation response to antigen-expressing leukemia or neuroblastoma cells, including CD25 upregulation, secretion of IFN-γ and TNF-α, release of cytolytic granules and growth inhibition, and overcame NK cell resistance of autologous leukemia cells while maintaining antigen specificity. These data indicate that the 2B4 receptor has a potent costimulatory effect in NK cells. Antigen-specific 2B4-ζ-expressing NK cells may be a powerful new tool for adoptive immunotherapy of leukemia and other malignancies.