Qiu Hui, Zhang Hui, Feng Zuo-hua, Geng Hui, Zhang Gui-mei
Department of Oncology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
Zhonghua Gan Zang Bing Za Zhi. 2006 Jul;14(7):505-9.
To explore the possible negative regulatory elements induced by the treatment of experimental murine hepatoma with 4-1BBL, and to investigate the synergistic effects and mechanisms of 4-1BBL and soluble PD-1 (sPD-1) in tumor therapy.
Mice were inoculated intramuscularly (i.m.) with 5 x 10(5) H22 tumor cells in the right hind thigh to establish the experimental hepatoma model. The mice were randomly divided into 5 groups (12 mice in each group) after inoculation. The mice of group A, B, C and D were injected with NS, plasmid pcDNA3.1, plasmid p4-1BBL and plasmid pPD-1A respectively. The mice in group E, the combinatorial treatment group, were injected with plasmid p4-1BBL and pPD-1A together. Then the anti-tumor effects, using the tumor growth rates and mice survival rates and others as parameters, were recorded. Meanwhile, the phenotype of lymphocytes and residual tumor cells in the peri-tumor tissue were analyzed.
Either transfection with 4-1BBL gene alone or with sPD-1 alone could inhibit tumor growth to some extent, but a more significant anticancer effect was obtained in the combinatorial treatment group (group E), in which the tumors were completely inhibited in 42% of the mice, compared with 0 in the other groups. In addition, the survival rate of mice in group E was 100%, compared with 30% in group B, 65% in group C and 62% in group D. The FACS analysis results showed that the expression level of B7-H1 and B7-DC on residual tumor cells in group C (injected with p4-1BBL alone) was higher than that on cells in other groups. The amount of CD8+ T cells in the peri-tumor tissue of group E was significantly increased.
4-1BBl can induce an up-regulation of negative regulatory elements and at the same time it can enhance the anti-tumor response. The combinatorial treatment with 4-1BBL and sPD-1 can produce a positive synergistic anti-tumor effect on our murine experimental hepatoma.
探讨用4-1BBL治疗实验性小鼠肝癌诱导的可能的负调控元件，并研究4-1BBL与可溶性程序性死亡受体-1（sPD-1）在肿瘤治疗中的协同作用及机制。
将5×10⁵个H22肿瘤细胞经右后大腿肌肉注射接种于小鼠，建立实验性肝癌模型。接种后将小鼠随机分为5组（每组12只）。A、B、C、D组小鼠分别注射生理盐水、质粒pcDNA3.1、质粒p4-1BBL和质粒pPD-1A。E组为联合治疗组，同时注射质粒p4-1BBL和pPD-1A。然后以肿瘤生长速率和小鼠存活率等为参数记录抗肿瘤效果。同时，分析肿瘤周围组织中淋巴细胞和残留肿瘤细胞的表型。
单独转染4-1BBL基因或单独转染sPD-1均可在一定程度上抑制肿瘤生长，但联合治疗组（E组）的抗癌效果更显著，其中42%的小鼠肿瘤完全被抑制，而其他组为0。此外，E组小鼠的存活率为100%，而B组为30%，C组为65%，D组为62%。流式细胞术分析结果显示，C组（单独注射p4-1BBL）残留肿瘤细胞上B7-H1和B7-DC的表达水平高于其他组细胞。E组肿瘤周围组织中CD8⁺T细胞数量显著增加。
4-1BBl可诱导负调控元件上调，同时增强抗肿瘤反应。4-1BBL与sPD-1联合治疗对我们的小鼠实验性肝癌可产生积极的协同抗肿瘤作用。
