Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b.
Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b.
复制标题
DOI：
10.1097/cji.0b013e3181ee6675
复制
发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Foster AE
中科院分区：
文献类型：
--
作者：
Craddock JA;Lu A;Bear A;Pule M;Brenner MK;Rooney CM;Foster AE
为了使过继性T细胞疗法对实体瘤有效，肿瘤特异性T细胞必须能够迁移到肿瘤部位。有效迁移的一个要求是效应细胞表达与肿瘤或肿瘤相关细胞产生的趋化因子相匹配的趋化因子受体。在这项研究中，我们研究了携带肿瘤抗原GD 2（GD 2-CAR）特异性嵌合抗原受体的活化T细胞（ATC）的肿瘤运输是否可以通过趋化因子受体CCR 2b的强制共表达来增强，因为该受体指导向CCL 2迁移，CCL 2是许多肿瘤（包括神经母细胞瘤）产生的趋化因子。神经母细胞瘤细胞系（SK-N-SH和SK-N-AS）和从六名患者分离的原代肿瘤细胞都分泌高水平的CCL 2，但GD 2-CAR转导的ATC缺乏CCR 2的表达（<5%）并且很少迁移到重组CCL 2或肿瘤上清液。然而，逆转录病毒转导后，ATCs表达高水平的CCR 2b（>60%），并在体外迁移良好。我们在表达CCR 2b的ATC中表达萤火虫荧光素酶，并观察到与CCR 2阴性ATC相比，向分泌CCL 2的神经母细胞瘤的归巢改善（>10倍）。因此，用CCR 2b和GD 2-CAR共修饰的ATC在体内具有更大的抗肿瘤活性。
For adoptive T cell therapy to be effective against solid tumors, tumor-specific T cells must be able to migrate to the tumor site. One requirement for efficient migration is that the effector cells express chemokine receptors that match the chemokines produced either by tumor or tumor-associated cells. In this study, we investigated whether the tumor trafficking of activated T cells (ATCs) bearing a chimeric antigen receptor specific for the tumor antigen GD2 (GD2-CAR) could be enhanced by forced co-expression of the chemokine receptor CCR2b, since this receptor directs migration towards CCL2, a chemokine produced by many tumors, including neuroblastoma. Neuroblastoma cell lines (SK-N-SH and SK-N-AS) and primary tumor cells isolated from six patients all secreted high levels of CCL2, but GD2-CAR transduced ATCs lacked expression of CCR2 (<5%) and migrated poorly to recombinant CCL2 or tumor supernatants. Following retroviral transduction, however, ATCs expressed high levels of CCR2b (>60%) and migrated well in vitro. We expressed firefly luciferase in CCR2b-expressing ATCs and observed improved homing (>10-fold) to CCL2-secreting neuroblastoma compared to CCR2 negative ATCs. As a result, ATCs co-modified with both CCR2b and GD2-CAR had greater anti-tumor activity in vivo.