Savai Rajkumar, Schermuly Ralph Theo, Pullamsetti Soni Savai, Schneider Michael, Greschus Susanne, Ghofrani Hossein Ardeschir, Traupe Horst, Grimminger Friedrich, Banat Gamal-Andre
Department of Hematology, Universitätsklinikum Giessen und Marburg GmbH, Giessen, Germany.
Cancer Res. 2007 Jun 1;67(11):5443-53. doi: 10.1158/0008-5472.CAN-06-3677.
Cancer immunotherapy with dendritic cell-tumor cell fusion hybrids induces polyclonal stimulation against a variety of tumor antigens, including unknown antigens. Hybrid cells can prime CTLs, which subsequently develop antitumor responses. The aim of this study was to enhance the known antitumor effect of hybrid vaccination (HC-Vacc) and hybrid-primed adoptive T-cell therapy (HC-ACT) using the poorly immunogenic Lewis lung carcinoma (LLC1) model. The strategy used was a combination of a double HC-Vacc alternating with HC-ACT (HC-Vacc/ACT). Using flat-panel volumetric computer tomography and immunohistochemistry, we showed a significant retardation of tumor growth (85%). In addition, a significant delay in tumor development, a reduction in the number of pulmonary metastases, and increased survival times were observed. Furthermore, the tumors displayed significant morphologic changes and increased apoptosis, as shown by up-regulation of gene expression of the proapoptotic markers Fas, caspase-8, and caspase-3. The residual tumor masses seen in the HC-Vacc/ACT-treated mice were infiltrated with CD4+ and CD8+ lymphocytes and showed elevated IFNgamma expression. Moreover, splenic enlargement observed in HC-Vacc/ACT-treated mice reflected the increased functionality of T cells, as also indicated by increased expression of markers for CTL activation, differentiation, and proliferation (Cd28, Icosl, Tnfrsf13, and Tnfsf14). Our findings indicate that the combination therapy of dendritic cell-tumor cell HC-Vacc/ACT is a very effective and a promising immunotherapeutic regimen against poorly immunogenic carcinomas.
用树突状细胞 - 肿瘤细胞融合杂交体进行癌症免疫治疗可诱导针对多种肿瘤抗原（包括未知抗原）的多克隆刺激。杂交细胞可启动细胞毒性T淋巴细胞（CTL），随后产生抗肿瘤反应。本研究的目的是利用免疫原性较差的刘易斯肺癌（LLC1）模型增强杂交疫苗接种（HC-Vacc）和杂交启动的过继性T细胞疗法（HC-ACT）已知的抗肿瘤效果。所采用的策略是将双重HC-Vacc与HC-ACT交替使用（HC-Vacc/ACT）。使用平板容积计算机断层扫描和免疫组织化学，我们显示肿瘤生长明显延缓（85%）。此外，观察到肿瘤发展显著延迟、肺转移数量减少以及存活时间延长。此外，肿瘤显示出明显的形态学变化和凋亡增加，促凋亡标志物Fas、半胱天冬酶 - 8和半胱天冬酶 - 3的基因表达上调表明了这一点。在接受HC-Vacc/ACT治疗的小鼠中看到的残留肿瘤块浸润有CD4+和CD8+淋巴细胞，并显示干扰素γ表达升高。此外，在接受HC-Vacc/ACT治疗的小鼠中观察到的脾肿大反映了T细胞功能的增强，CTL激活、分化和增殖标志物（Cd28、Icosl、Tnfrsf13和Tnfsf14）表达增加也表明了这一点。我们的研究结果表明，树突状细胞 - 肿瘤细胞HC-Vacc/ACT联合疗法是一种针对免疫原性较差的癌症非常有效且有前景的免疫治疗方案。
