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目的探讨sPD-1和4-1BBL联合治疗肿瘤的效应和相关的免疫学机制。方法以H22肝癌细胞接种于BALB／c小鼠右后腿肌肉内,建立小鼠肿瘤模型;采用4-1BBL和可溶性PD-1(sPD- 1)真核表达质粒通过肌肉转染进行基因治疗;检测小鼠肿瘤生长情况,并检测转染基因及肿瘤微环境中免疫调控相关基因的表达,检测肿瘤组织中的淋巴细胞数量的变化。结果单独转染4-1BBL基因或sPD-1基因均显示出抗肿瘤作用,而联合治疗对肿瘤生长抑制作用更为明显,该组抑瘤率高达92．3％(以pcDNA3．1组为对照),显著高于4-1BBL组(78％)、sPD-1组(70．2％)。联合治疗不仅使TGF-β、IL-10的表达下调,而且在治疗后期更有效地促进IFN-γ和IL-2基因表达上调,且使瘤组织中CD8+T淋巴细胞数量较其他各组显著增加。结论4-1BBL和sPD-1联合治疗可使肿瘤微环境中的免疫相关基因表达更有利于抗肿瘤免疫应答,增强肿瘤免疫治疗效果。
Objective To investigate the effect of sPD-1 and 4-1BBL combination on tumor and related immunological mechanisms. Methods H22 hepatocarcinoma cells were inoculated into the muscle of the right hind leg of BALB / c mice to establish a mouse tumor model. Gene therapy was performed by muscle transfection with 4-1BBL and soluble PD-1 (sPD-1) eukaryotic expression plasmid. Tumor growth was detected in mice, and the expression of genes related to immune regulation and the number of lymphocytes in the tumor microenvironment were detected. Results The results showed that antitumor effect of 4-1BBL gene or sPD-1 gene alone was found, however, combination therapy had a more obvious inhibitory effect on tumor growth, with a tumor inhibition rate as high as 92.3% (compared with pcDNA3.1 group ), Significantly higher than 4-1BBL group (78%), sPD-1 group (70.2%). Combination therapy not only down-regulated the expression of TGF-β and IL-10, but also promoted the upregulation of IFN-γ and IL-2 gene more effectively in the later period of treatment, and significantly increased the number of CD8 + T lymphocytes in the tumor tissue compared with other groups increase. Conclusions The combination of 4-1BBL and sPD-1 can make immune-related gene expression in tumor microenvironment more favorable to anti-tumor immune response and enhance the effect of tumor immunotherapy.