Cure of mammary carcinomas in Her-2 transgenic mice through sequential stimulation of innate (neoadjuvant interleukin-12) and adaptive (DNA vaccine electroporation) immunity
Cure of mammary carcinomas in Her-2 transgenic mice through sequential stimulation of innate (neoadjuvant interleukin-12) and adaptive (DNA vaccine electroporation) immunity
复制标题
DOI：
10.1158/1078-0432.ccr-04-1873
复制
发表时间：
2005-03-01
影响因子：
11.5
通讯作者：
Forni, G
中科院分区：
文献类型：
--
作者：
Spadaro, M;Ambrosino, E;Forni, G
目的：尽管新辅助治疗正在成为早期原发性乳腺癌的一种治疗选择，但在新辅助治疗中使用抗血管生成剂和免疫调节剂的数据尚不可用。在Her-2自发性乳腺癌的模型中，我们研究了新辅助白细胞介素12（IL-12）的疗效，然后通过“免疫手术”的残留tumor.Experimental Design：雌性BALB/c小鼠转基因大鼠Her-2癌基因无情地发展浸润性癌在所有的乳腺由23周龄。患有多灶性原位癌的小鼠接受每周四次的100 ng IL-12腹膜内注射，随后休息3周。这门课开了四次。一些小鼠另外收到的DNA质粒编码部分的Her-2受体电穿孔通过transcutaneous electric pulses.Results：IL-12引起的保护与两个DNA疫苗电穿孔的组合保持63%的小鼠无肿瘤。当IL-12处理的小鼠接受四次疫苗电穿孔时，实现了对所有1岁小鼠的完全保护。病理学发现、体外试验、IFN-If和免疫球蛋白基因敲除转基因小鼠的免疫接种和过继转移实验的结果均表明，IL-12增强了由疫苗接种引起的B-和T-细胞应答，并略微降低了调节性T细胞的数量。此外，IL-12强烈抑制肿瘤angiogenesis.Conclusions：在Her-2转基因小鼠，IL-12损害肿瘤的进展，并触发先天免疫，使显着的DNA疫苗成为有效的，在晚些时候，它是无效的。
Purpose: Whereas neoadjuvant therapy is emerging as a treatment option in early primary breast cancer, no data are available on the use of antiangiogenic and immunomodulatory agents in a neoadjuvant setting. In a model of Her-2 spontaneous mammary cancer, we investigated the efficacy of neoadjuvant interleukin 12 (IL-12) followed by "immune-surgery" of the residual tumor.Experimental Design: Female BALB/c mice transgenic for the rat Her-2 oncogene inexorably develop invasive carcinomas in all their mammary glands by the 23rd week of age. Mice with multifocal in situ carcinomas received four weekly i.p. injections of 100 ng IL-12 followed by a 3-week rest. This course was given four times. A few mice additionally received DNA plasmids encoding portions of the Her-2 receptor electroporated through transcutaneous electric pulses.Results: The protection elicited by IL-12 in combination with two DNA vaccine electroporations kept 63% of mice tumor-free. Complete protection of all 1-year-old mice was achieved when IL-12-treated mice received four vaccine electroporations. Pathologic findings, in vitro tests, and the results from immunization of both IFN-If and immunoglobulin gene knockout transgenic mice and of adoptive transfer experiments all show that IL-12 augments the B- and T-cell response elicited by vaccination and slightly decreases the number of regulatory T cells. In addition, IL-12 strongly inhibits tumor angiogenesis.Conclusions: In Her-2 transgenic mice, IL-12 impairs tumor progression and triggers innate immunity so markedly that DNA vaccination becomes effective at late points in time when it is ineffective on its own.