Xiao Han, Huang Bo, Yuan Ye, Li Dong, Han Ling-Fei, Liu Yi, Gong Wei, Wu Feng-Hua, Zhang Gui-Mei, Feng Zuo-Hua
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Clin Cancer Res. 2007 Mar 15;13(6):1823-30. doi: 10.1158/1078-0432.CCR-06-2154. Epub 2007 Feb 26.
The use of costimulatory molecules targeting distinct T-cell signaling pathways has provided a means for triggering and enhancing antitumor immunity; however, it is still not fully understood what types of costimulatory molecules are suitable for the combination in tumor therapy. Our purpose in this study is to establish an effective antitumor immune approach by using costimulatory molecule 4-1BBL in combination with soluble PD-1.
The murine H22 hepatocarcinoma served as an ectopic tumor model. Local gene transfer was done by injection with naked plasmid p4-1BBL and/or psPD-1. The synergistic mechanism of dual-gene therapy was elucidated by detecting the change of gene expression of immunoregulatory factors in tumor microenvironment. The effects of immunotherapy were evaluated by testing the function of tumor-specific T cells, measuring tumor weight or volume, survival of mice, and H&E staining of tissues.
4-1BBL expressed by normal nonimmune cells effectively enhanced antitumor immune response but up-regulated PD-L1 and did not reduce IL-10 and transforming growth factor-beta (TGF-beta). sPD-1 synergized with 4-1BBL to establish efficient antitumor immune environment, including down-regulation of IL-10 and TGF-beta, further up-regulation of interleukin (IL)-2 and IFN-gamma, and higher CD8(+) T-cell infiltration. The combined treatment by 4-1BBL/sPD-1 eradicated tumors from mice with small amounts of preexistent tumor cells or tumors from approximately 60% of individuals with larger amounts of preexistent tumor cells.
Our findings in this report imply a great potential of 4-1BBL in combination with sPD-1 in tumor therapeutics with the in vivo existent tumor cells as antigens.
使用靶向不同T细胞信号通路的共刺激分子为触发和增强抗肿瘤免疫提供了一种手段；然而，对于哪些类型的共刺激分子适合联合用于肿瘤治疗仍未完全了解。本研究的目的是通过使用共刺激分子4-1BBL与可溶性PD-1联合来建立一种有效的抗肿瘤免疫方法。
小鼠H22肝癌作为异位肿瘤模型。通过注射裸质粒p4-1BBL和/或psPD-1进行局部基因转移。通过检测肿瘤微环境中免疫调节因子基因表达的变化来阐明双基因治疗的协同机制。通过测试肿瘤特异性T细胞的功能、测量肿瘤重量或体积、小鼠存活情况以及组织的苏木精-伊红染色来评估免疫治疗的效果。
正常非免疫细胞表达的4-1BBL有效地增强了抗肿瘤免疫反应，但上调了PD-L1且未降低IL-10和转化生长因子-β（TGF-β）。sPD-1与4-1BBL协同建立了有效的抗肿瘤免疫环境，包括下调IL-10和TGF-β、进一步上调白细胞介素（IL）-2和干扰素-γ以及更高的CD8(+) T细胞浸润。4-1BBL/sPD-1联合治疗根除了具有少量预先存在肿瘤细胞的小鼠体内的肿瘤，或根除了约60%具有大量预先存在肿瘤细胞个体体内的肿瘤。
我们在本报告中的发现表明，4-1BBL与sPD-1联合在以体内存在的肿瘤细胞为抗原的肿瘤治疗中具有巨大潜力。
