Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer.
Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer.
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DOI：
10.1084/jem.173.5.1047
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发表时间：
1991-05-01
期刊：
影响因子：
--
通讯作者：
Diamantstein T
中科院分区：
文献类型：
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作者：
Blankenstein T;Qin ZH;Uberla K;Müller W;Rosen H;Volk HD;Diamantstein T
通过逆转录病毒基因转移将肿瘤坏死因子α（TNF-α）基因导入TNF-α不敏感的肿瘤细胞系J558L中。克隆 J2T12 产生的 40 pg/ml TNF-α 始终不会改变体外生长速率，但注射到同系 BALB/c 小鼠中时会显着抑制肿瘤生长。 2周内，接种J558L细胞的小鼠中有90%出现肿瘤，但注射J2T12的小鼠均未出现肿瘤。在观察期内（大于3个月），接种J2T12的小鼠中有60%没有出现肿瘤。在另外 40% 的小鼠中，肿瘤的表现明显延迟。同时注射 J2T12 细胞和抗 TNF-α 单克隆抗体的小鼠产生了与亲代 J558L 细胞相似的肿瘤。类似地，TNF-α的肿瘤抑制作用被消除，例如通过注射抗3型补体受体（CR3）单克隆抗体，已知该抗体可防止炎症细胞迁移。这些结果和对肿瘤浸润巨噬细胞的观察表明，J2T12细胞缺乏致瘤性是由于肿瘤细胞分泌TNF-α，并且TNF-α通过涉及细胞（主要是巨噬细胞）趋化募集和激活的机制间接发挥作用。相比之下，当J558L细胞表达白细胞介素6而不是TNF-α时，肿瘤生长没有受到影响。总之，我们的结果支持了肿瘤细胞靶向细胞因子基因转移作为癌症治疗工具的概念，并特别证明了肿瘤细胞产生的极低剂量的 TNF-α 足以抑制肿瘤生长，而没有可检测到的副作用。
The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF- alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor- infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF- alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.