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首页> 外文期刊>Cancer gene therapy >Antitumor immune responses mediated by adenoviral GDEPT using nitroreductase|[sol]|CB1954 is enhanced by high-level coexpression of heat shock protein 70
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Antitumor immune responses mediated by adenoviral GDEPT using nitroreductase|[sol]|CB1954 is enhanced by high-level coexpression of heat shock protein 70

机译：高水平共表达热休克蛋白70增强了使用亚硝基还原酶| [sol] | CB1954的腺病毒GDEPT介导的抗肿瘤免疫应答

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Gene-directed enzyme prodrug therapy (GDEPT) is a promising approach to local management of cancer through targeted chemotherapy. Killing localized tumors by GDEPT in a manner that induces strong antitumor cellular immune responses might improve local management and allow benefit in disseminated cancer. Here we evaluated the combination of nitroreductase (NTR)/CB1954 GDEPT with high-level expression of heat shock protein 70 (HSP70, a stress protein that can shuttle cytosolic peptides into antigen-presenting cells) for induction of antitumor immunity using adenovirus gene delivery in an aggressive and nonimmunogenic BALB/c syngeneic 4T1 breast cancer model. The mechanism of cell death and spectrum of stress proteins induced are likely to be important determinants of the resulting immune responses. We showed that NTR/CB1954 treatment of 4T1 cells gave both apoptotic and nonapoptotic killing. In vivo killing of 4T1 cells expressing NTR gave weak antitumor immunity and very limited induction of stress proteins including HSP70. High-level coexpression of HSP70 during NTR/CB1954-mediated killing of 4T1 cells in vivo gave much greater protection from tumor challenge (67% long-term survivors compared to 17%) and induced 4T1-specific cytotoxic T-cell responses. The enhancement of antitumor responses resulting from HSP70 coexpression was similar to that conferred by coexpression of GM-CSF.
机译：基因导向的酶前药疗法（GDEPT）是一种通过靶向化学疗法对癌症进行局部治疗的有前途的方法。通过GDEPT杀死局部肿瘤的方法可以诱导强烈的抗肿瘤细胞免疫反应，这可能会改善局部管理，并有利于弥散性癌症。在这里，我们评估了硝基还原酶（NTR）/ CB1954 GDEPT与高水平表达的热休克蛋白70（HSP70，一种可以将细胞溶质肽穿梭到抗原呈递细胞中的应激蛋白）的结合，使用腺病毒基因递送诱导抗肿瘤免疫。侵袭性和非免疫原性的BALB / c同基因4T1乳腺癌模型。细胞死亡的机制和诱导的应激蛋白谱很可能是最终免疫反应的重要决定因素。我们显示，NTR / CB1954对4T1细胞的处理可导致凋亡和非凋亡杀伤。在体内杀死表达NTR的4T1细胞会产生较弱的抗肿瘤免疫力，并且对包括HSP70在内的应激蛋白的诱导作用非常有限。在NTR / CB1954介导的4T1细胞体内杀伤过程中，HSP70的高水平共表达为肿瘤攻击提供了更大的保护（67％的长期存活者与17％的长期存活者相比），并诱导了4T1特异性细胞毒性T细胞反应。 HSP70共表达导致的抗肿瘤​​反应增强与GM-CSF共表达所引起的增强类似。

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