Zhang Guojun, Xu Mingkai, Song Yubo, Su Zhencheng, Zhang Huiwen, Zhang Chenggang
Institute of Applied Ecology, Chinese Academy of Sciences, No.72 Wenhua Road Shenhe Dis., Shenyang, Liaoning, 110016, People's Republic of China.
University of Chinese Academy of Sciences, Beijing, China.
Appl Microbiol Biotechnol. 2016 Mar;100(6):2677-84. doi: 10.1007/s00253-015-7104-1. Epub 2015 Nov 4.
Staphylococcal enterotoxins C2 (SEC2) is a classical model of superantigens (SAg), which has the powerful ability to activate T cells as well as induce massive cytokine production. This property makes SEC2 and its mutants well concerned as a potential new immune-regulatory agent for cancer therapy. We previously constructed a SEC2 mutant named SAM-3, which had prominently antitumor activity in BALB/c mice model. But, the underlying molecular mechanism for stimulation of human peripheral blood mononuclear cells (PBMCs) and antitumor effect on human tumor cells induced by SAM-3 is not clear. Here, we showed that SAM-3 could activate human TCR Vβ 12, 13A, 14, 15, 17, and 20 CD8(+) subgroup T cells, which secreted the cytokines IL-2, IFN-γ, and TNF-α, and exhibit stimulation activity in a dose-dependent manner. TNF-α secreted from activated T cells could induce apoptosis and G1-phase arrest and lead to the antitumor effect in HepG2 cells. Meanwhile, SAM-3 upregulated the expression of tumor necrosis factor receptor 1 (TNFR1) mRNA and activity of caspase-3 and caspase-8. We also found that the antitumor activity and activity of caspase-3 and caspase-8 were decreased when the neutralizing TNF-α monoclonal antibody presented. These data suggest that TNF-α secreted by SAM-3-activated T cells is an important factor in inducing apoptosis in HepG2 cells.
葡萄球菌肠毒素C2（SEC2）是超抗原（SAg）的经典模型，它具有强大的激活T细胞以及诱导大量细胞因子产生的能力。这一特性使得SEC2及其突变体作为一种潜在的癌症治疗新免疫调节药物备受关注。我们之前构建了一个名为SAM-3的SEC2突变体，它在BALB/c小鼠模型中具有显著的抗肿瘤活性。但是，SAM-3刺激人外周血单个核细胞（PBMCs）以及对人肿瘤细胞产生抗肿瘤作用的潜在分子机制尚不清楚。在此，我们表明SAM-3可以激活人TCR Vβ 12、13A、14、15、17和20 CD8(+)亚群T细胞，这些细胞分泌细胞因子IL-2、IFN-γ和TNF-α，并呈剂量依赖性地表现出刺激活性。活化T细胞分泌的TNF-α可诱导HepG2细胞凋亡和G1期阻滞并导致抗肿瘤作用。同时，SAM-3上调肿瘤坏死因子受体1（TNFR1）mRNA的表达以及caspase-3和caspase-8的活性。我们还发现，当存在中和TNF-α单克隆抗体时，SAM-3的抗肿瘤活性以及caspase-3和caspase-8的活性降低。这些数据表明，SAM-3激活的T细胞分泌的TNF-α是诱导HepG2细胞凋亡的重要因素。
