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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >Generation of cytotoxic effector lymphocytes by MLTC using tumor cells genetically modified to secrete interleukin-2.
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Generation of cytotoxic effector lymphocytes by MLTC using tumor cells genetically modified to secrete interleukin-2.

机译：MLTC使用经过基因修饰以分泌白介素2的肿瘤细胞通过MLTC产生细胞毒性效应淋巴细胞。

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The in vitro generation of effector lymphocytes cytotoxic to cancer cells, was investigated with a mixed lymphocyte-tumor culture (MLTC) system using genetically modified human cancer cells, followed by stimulation with the interleukin (IL)-2 plus immobilized anti-CD3 antibody (IL-2/CD3) system. A gastric cancer cell line, GC022588 (HLA-A2, 24, B35, 55, C1,3), was retrovirally transduced with the human interleukin (IL)-2 gene (GC/IL-2) or the neomycin-resistance gene (GC/Neo). The secretion of biologically active IL-2 was detectable in GC/IL-2 cells but not in GC/Neo or parental GC022588 cells. The cytotoxic activity against the parental GC022588 cells of peripheral blood mononuclear cells (PBMC) was greater among PBMC activated with MLTC using GC/IL-2 than among those activated with MLTC using GC/Neo or without MLTC. The IL-2/CD3 stimulation could efficiently expand the effector lymphocytes without any reduction of the cytotoxic activity generated. The cytotoxic activity generated by this system was reproducible in several HLA-A2- or A24-positive donors. The effector lymphocytes could kill the other adenocarcinoma cells expressing HLA-A2 or A24. The phenotypes of the effector lymphocytes generated with the system were 40% CD4+ and 70% CD8+. Both phenotypes may have been responsible for the cytotoxicity. The removal of adherent cells from PBMC before the MLTC did not affect the generation of cytotoxicity, whereas neutralization of tumor-derived IL-2 with a specific antibody during the MLTC significantly inhibited the generation of cytotoxicity. These results suggest that IL-2 gene-transduction augments the immunogenicity of the tumor cells that efficiently stimulate lymphocytes to be cytotoxic, and that the IL-2/CD3 system may be practical for the expansion of effector lymphocytes for use in adoptive immunotherapy for cancer. The mechanism by which IL-2 gene-modified tumor cells stimulate immune reactivity was discussed.
机译：使用基因修饰的人类癌细胞，通过混合淋巴细胞-肿瘤培养（MLTC）系统研究了对癌细胞具有细胞毒性的效应淋巴细胞的体外生成，然后用白介素（IL）-2加上固定的抗CD3抗体进行刺激（ IL-2 / CD3）系统。用人白介素（IL）-2基因（GC / IL-2）或抗新霉素基因（GC / MS-2）逆转录病毒转导胃癌细胞系GC022588（HLA-A2，24，B35，55，C1,3） GC / Neo）。在GC / IL-2细胞中可检测到具有生物活性的IL-2分泌，但在GC / Neo或亲本GC022588细胞中未检测到。在使用GC / IL-2的MLTC激活的PBMC中，对外周血单核细胞（PBMC）亲本GC022588细胞的细胞毒活性要比在使用GC / Neo或不使用MLTC的MLTC激活的PBMC中更高。 IL-2 / CD3刺激可有效扩增效应淋巴细胞，而不会降低产生的细胞毒性活性。该系统产生的细胞毒活性在几个HLA-A2-或A24阳性供体中可重现。效应淋巴细胞可以杀死其他表达HLA-A2或A24的腺癌细胞。系统产生的效应淋巴细胞的表型为40％CD4 +和70％CD8 +。两种表型可能是造成细胞毒性的原因。在MLTC之前从PBMC去除粘附细胞不会影响细胞毒性的产生，而在MLTC期间用特异性抗体中和肿瘤衍生的IL-2会明显抑制细胞毒性的产生。这些结果表明IL-2基因转导增强了有效刺激淋巴细胞具有细胞毒性的肿瘤细胞的免疫原性，并且IL-2 / CD3系统可能对于扩大效应淋巴细胞以用于癌症的过继免疫疗法是实用的。 。讨论了IL-2基因修饰的肿瘤细胞刺激免疫反应性的机制。

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