Pseudomonas aeruginosa Mannose-Sensitive Hemagglutinin Promotes T-Cell Response via Toll-Like Receptor 4-Mediated Dendritic Cells to Slow Tumor Progression in Mice
Pseudomonas aeruginosa Mannose-Sensitive Hemagglutinin Promotes T-Cell Response via Toll-Like Receptor 4-Mediated Dendritic Cells to Slow Tumor Progression in Mice
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DOI：
10.1124/jpet.113.212316
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发表时间：
2014-05-01
影响因子：
3.5
通讯作者：
Chu, Yiwei
中科院分区：
文献类型：
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作者：
Zhang, Min;Luo, Feifei;Chu, Yiwei
铜绿假单胞菌甘露糖敏感血凝素(PA-MSHA)作为一种可杀伤肿瘤细胞的药物已在临床应用。然而，PA-MSHA的抗肿瘤免疫应答尚不完全清楚。在这项研究中，我们发现用PA-MSHA加3LL抗原治疗Lewis肺癌(3LL)小鼠可以减缓肿瘤进展并延长生存期。PA-MSHA治疗后，肿瘤部位T细胞数量和树突状细胞成熟均显著增加。此外，PA-MSHA体外刺激可使幼龄小鼠骨髓来源的树突状细胞(BMDCs)成熟，具有更高的共刺激分子表达，更多的细胞因子分泌，更低的内吞活性，以及更强的增强T细胞激活的能力。成熟过程中需要Toll样受体(TLR4)，而不需要TLR2。更重要的是，PA-MSHA诱导的DC对于PA-MSHA促进TLR4介导的T细胞的活化、扩增和干扰素-γ的分泌是必不可少的，这在PA-MSHA的抗肿瘤作用中起着重要作用。因此，本研究揭示了PA-MSHA是一种新型的TLR4激动剂，可以诱导抗肿瘤免疫反应来减缓肿瘤的进展。
Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) as a drug may kill tumor cells and has been used clinically. However, the antitumor immune response of PA-MSHA is not completely understood. In this study, we found that treating Lewis lung carcinoma (3LL)-bearing mice with PA-MSHA plus 3LL antigen led to slower tumor progression and longer survival. After PA-MSHA treatment, T-cell number and dendritic cell maturation were both increased significantly at the tumor site. In addition, PA-MSHA in vitro stimulation resulted in the maturation of bone marrow-derived dendritic cells (BMDCs) from naive mice, showing higher costimulatory molecule expression, more cytokine secretion, lower endocytic activity, and stronger capacity to enhance T-cell activation. Toll-like receptor (TLR)4 but not TLR2 was required in the maturation process. More importantly, PA-MSHA-induced DCs were essential for PA-MSHA to enhance activation, expansion, and interferon (IFN)-gamma secretion of TLR4-mediated T cells, which play a role in the antitumor effect of PA-MSHA. Thus, this study reveals PA-MSHA as a novel TLR4 agonist that elicits antitumor immune response to slow tumor progression.