阻断Treg细胞和肿瘤细胞表面的TNFR2受体可特异性抑制肿瘤组织中Treg细胞并杀死肿瘤细胞，提示TNFR2是有效且特异的抗肿瘤靶点。已知Treg介导的免疫抑制效应是促进恶性胸腔积液（MPE）进展的重要机制。我们发现MPE中Treg细胞高表达TNFR2，与其增殖能力显著正相关，且MPE中Th17表达的TNF-α与Treg水平正相关性最强。TNF-α可经TNFR2上调肿瘤细胞表面黏附分子，增强癌细胞侵袭能力。这些结果提示MPE中TNF-α/TNFR2信号通路参与调控T淋巴细胞和肿瘤细胞的活性，但具体机制、对MPE形成的影响、阻断TNFR2的效应均未知晓。项目组将深入研究MPE中TNF-α/TNFR2通路对Treg细胞增殖、分化和功能的影响；各细胞亚群间经此通路相互作用的方式和效应；及对肿瘤细胞增殖、凋亡和侵袭的影响。从多方面评估TNFR2抑制剂在MPE治疗中的效果，为MPE治疗寻找新靶点。

Tumor necrosis factor receptor type II (TNFR2) antagonists were identified to specifically inhibit Tregs expansion in the tumor microenvironment, and killed human tumor cells directly, indicated that TNFR2 might be an effective and specific target for cancer immunotherapy. Previous studies demonstrated that Treg mediated the immunosuppressive responses which is an important mechanism to promote the formation of malignant pleural effusion(MPE). Our primary data indicated that the level of TNFR2 expression on Tregs was significantly higher than the other cell subsets in MPE, which was correlated with the proliferative capacity positively. Furthermore, there was a strong positive correlation between TNF-α expressed by Th17 cells and Foxp3 expressed by Tregs. Additionally, TNF-α increased the level of adhesion molecules on tumor cells and enhanced the ability of migration and invasion. These results suggest that TNF-α/TNFR2 signaling pathway may involve in regulating the activity of T lymphocytes and tumor cells, however the concrete mechanisms, the roles in the formation of MPE and the effects after blocking TNFR2 remain unclear. On the basis of our previous studies, we 1) will investigate the effects of TNF-α/TNFR2 pathway on the proliferation, differentiation and function of Treg cells in MPE; 2) will explore the modes and effects of the interactions among the cell subsets in MPE via TNF-α/TNFR2 pathway; 3) will elucidate the effects of TNF-α/TNFR2 pathway on the proliferation, apoptosis, migration and invasion of tumor cells; 4) will evaluate the treatment efficacy of targeting TNFR2 for MPE therapy in many aspects; 5) will try to find out a novel and effective targeting molecule for managing MPE.