Cao X, Wang Q, Ju D W, Tao Q, Wang J
Dept. of Immunology, Second Military Medical University, Shanghai, P.R. China.
J Exp Clin Cancer Res. 1999 Jun;18(2):191-200.
Interleukin 2 (IL-2) expressing plasmid and interleukin 6 (IL-6)-expressing plasmid were encapsulated in liposome and administrated intratumoraly into tumor-bearing mice 4 days after subcutaneous inoculation of B16F10 melanoma cells. The results showed that treatment of tumor-bearing mice with IL-2 gene or IL-6 gene transfer inhibited the growth of subcutaneous tumor and prolonged the survival of tumor-bearing mice significantly when compared with the treatment of PBS or control gene transfer mediated by liposome (P < 0.01). Combined transfer of IL-2 gene and IL-6 gene was found to elicit inhibitory effects on the growth of B16F10 tumor more significantly and prolonged the survival period of tumor-bearing mice more obviously. We investigated the local immunity in tumor microenvironment and found that IL-2 and IL-6 gene transfer could significantly increase the expression of lymphocyte function-associated antigen-1 on tumor infiltrating lymphocytes (TIL) and MHC-I molecule on tumor cells freshly isolated from the tumor mass. The NK and CTL activity of TIL increased markedly after the combined transfer of these two cytokine genes. We also observed the systemic antitumor immune response in the tumor-bearing mice and demonstrated that NK and CTL activity of splenocytes and the production of IL-2, tumor necrosis factor and interferon-gamma from splenocytes increased obviously in mice after the combined transfer of IL-2 and IL-6 gene. In conclusion, local and systemic antitumor immunity of the tumor-bearing host could be induced efficiently after the combined gene transfer. The enhanced specific and non-specific antitumor immunity might be responsible for the more potent antitumor effects of the combined gene therapy.
将表达白细胞介素2（IL-2）的质粒和表达白细胞介素6（IL-6）的质粒包裹在脂质体中，并在皮下接种B16F10黑色素瘤细胞4天后瘤内注射给荷瘤小鼠。结果显示，与用PBS或脂质体介导的对照基因转移治疗相比，用IL-2基因或IL-6基因转移治疗荷瘤小鼠可显著抑制皮下肿瘤生长并延长荷瘤小鼠的生存期（P<0.01）。发现IL-2基因和IL-6基因联合转移对B16F10肿瘤生长的抑制作用更显著，且更明显地延长了荷瘤小鼠的生存期。我们研究了肿瘤微环境中的局部免疫，发现IL-2和IL-6基因转移可显著增加肿瘤浸润淋巴细胞（TIL）上淋巴细胞功能相关抗原-1的表达以及从肿瘤块中新鲜分离的肿瘤细胞上MHC-I分子的表达。这两种细胞因子基因联合转移后，TIL的NK和CTL活性显著增加。我们还观察了荷瘤小鼠的全身抗肿瘤免疫反应，证明IL-2和IL-6基因联合转移后，小鼠脾细胞的NK和CTL活性以及脾细胞中IL-2、肿瘤坏死因子和干扰素-γ的产生明显增加。总之，联合基因转移后可有效诱导荷瘤宿主的局部和全身抗肿瘤免疫。增强的特异性和非特异性抗肿瘤免疫可能是联合基因治疗更强抗肿瘤作用的原因。
