肿瘤抗原多肽致敏白细胞介素18基因修饰的树突状细胞治疗小鼠转移性肺癌

目的探讨肿瘤多肽致敏的白细胞介素18(IL-18)基因修饰的树突状细胞(DC)对自发性肺转移癌的治疗作用。方法小鼠足垫注射3LLLewis肺癌细胞建立自发性肺转移癌模型，经骨髓来源的IL-18基因修饰、3LL特异抗原多肽Mut1体外致敏DC(DC-IL-18/Mut1)皮下免疫2次，观察荷瘤鼠肺脏重量、肺表面转移结节、存活期的变化及相应免疫指标等变化，实验分8组，组间差异行t检验,生存期行时序检验。结果与对照病毒组(DC-LacZ/Mut1)及未处理DC组相比，DC-IL-18/Mut1组肺脏重量最轻(215mg±20mg与398mg±23mg和987mg±45mg比较，t值分别为14.7及38.4，P均<0.01)、肺表面转移结节最少(0与7.8±2.7和49.4±4.3比较,t值分别为7.07及16.2，P均<0.01)、存活期最长(χ2分别为6.78、10.49，P均<0.01)，其诱导细胞毒性T淋巴细胞(CTL)活性(53.4±3.1与41.3±2.6和9.8±2.1比较,t值分别为7.3及28.5,P均<0.01)和天然杀伤细胞(NK)活性(35.8±2.4与15.6±2.8及13.6±2.5比较,t值分别为13.4及15.7，P均<0.01)最显著，且CD4+T、CD8+T及NK细胞比例增加。结论MHCⅠ类限制性肿瘤抗原多肽致敏的IL-18基因修饰的DC能通过诱导显著的抗肿瘤免疫反应而对自发性肺转移癌有明显的治疗作用。

Treatment of spontaneous metastatic lung cancer with tumor antigen-pulsed, interleukin-18 gene-modified dendritic cells

OBJECTIVE: To investigate the effect of tumor antigen-pulsed, interleukin-18 (IL-18) gene-modified dendritic cells in treatment of spontaneous metastatic lung cancer. METHODS: 3LL Lewis lung cancer cells were injected into the footpads of C57BL/6 mice to establish a spontaneous metastatic lung cancer model. Ninety-six mice with lung cancer were divided into 8 groups, 12 in each. treated differently. One group was treated by subcutaneous vaccination for two times of tumor antigen peptide Mut1-pulsed, IL-18 gene-modified dendritic cells (DC-IL-18/Mut1) that were derived from normal bone marrow. The other groups were treated with other measures. After treatment, the lung weight, number of metastatic nodes on the lung surface, survival time, and NK and CTL activities were examined. RESULTS: Compared with the mice treated with Mut1-pulsed control LacZ gene-modified DC and those treated with untreated DC, the tumor-bearing mice treated with DC-IL-18/Mut1 had the lightest lung weight (215 mg +/- 20 mg Vs 398 mg +/- 23 mg and 987 mg +/- 45 mg, t = 14.7 and 38.4, P < 0.01), the least lung metastatic nodes (0 Vs 7.8 +/- 2.7 and 49, P < 0.01), the longest survival time (chi(2) = 6.78 and 10.49 respectively, P < 0.01), the strongest cytotoxic T cell activity (53.4 +/- 3.1 Vs 41.3 +/- 2.6 and 9.8 +/- 2.1, t = 13.4 and 15, 7 respectively, P < 0.01), and increased proportions of CD4 + Tcells, CD8 + Tcells, and NK cells. CONCLUSION: Tumor antigen-pulsed, IL-18 gene-modified dendritic cells have a significant therapeutic effect on spontaneous netastatic lung cancer through induction of anti-tumor immunological responses.