Forced expression of the TNF-family gene in lung cancer cells produced therapeutic effects, stimulating antigen-presentation processes.

诱导负责细胞介导免疫的细胞毒性T细胞需要激活树突状细胞（DC），树突状细胞在抗原呈递中起着至关重要的作用。我们在本研究中考察了DC是否可以通过tnf家族基因的基因转移来激活，从而对肺癌细胞产生抗肿瘤作用。用tnf家族基因转染小鼠肺癌Lewis细胞，并将建立的克隆皮下接种于同基因小鼠。CD40配体表达的肿瘤与母肿瘤相比生长明显迟缓，自发性肺转移灶数量明显减少。接种Fas配体表达肿瘤的免疫活性小鼠未发生肿瘤，小鼠产生肿瘤特异性保护性免疫。小鼠未产生任何肺转移灶。TNF-α-表达肿瘤的生长情况与原代肿瘤无明显差异，但转移灶数量明显减少。为了分析DC在这种抗肿瘤作用中的作用，我们将从骨髓细胞中获得的DC与转染的细胞共培养。DC与Fas配体表达而非亲本肿瘤形成簇。CD86是DC的激活标记和共刺激分子，在与CD40配体表达的肿瘤共培养过程中，CD86的表达上调。Fas配体和CD40配体似乎分别参与DC的抗原加工和成熟。

Induction of cytotoxic T cells, responsible for cell-mediated immunity, requires the activation of dendritic cells (DC) which play a crucial role in antigen-presentation. We examined in this study whether activation of DC could be performed by gene transfer of the TNF-family gene and consequently antitumor effects were produced against lung cancer cells. Murine lung carcinoma Lewis cells were transfected with the TNF-family gene and established clones were subcutaneously inoculated into syngeneic mice. The growth of CD40 ligand-expressed tumors was significantly retarded compared with that of parent tumors and the number of spontaneous lung metastatic foci was significantly reduced. The immunocompetent mice that were inoculated with the Fas ligand-expressed tumors did not developed tumors and the mice generated tumor-specific protective immunity. The mice did not produce any lung metastatic foci. The growth of the TNF-α-expressed tumors was not different from that of parent tumors but the number of metastatic foci was significantly decreased. In order to analyze the involvement of DC in this antitumor effects, we cocultured DC that were obtained from bone-marrow cells with the transfected cells. DC formed cluster with Fas ligand-expressed but not parent tumors. The expression of CD86, an activation marker an costimulatory molecule of DC, was upregulated during the coculture with CD40 ligand-expressed tumors. Fas ligand and CD40 ligand seem to be involved in antigen processing and maturation of DC, respectively.