肿瘤相关性炎症微环境下机体免疫系统易发生由抗肿瘤向促肿瘤的功能转向，但是介导这种转向的分子机制尚不明确。基于前期研究结果，本课题拟通过不同类型的小鼠肿瘤模型，并结合临床样本考察在肿瘤相关性炎症微环境中SHP-2与抗肿瘤免疫功能转向促瘤的相关性，以期确定SHP-2是决定肿瘤免疫走向的关键分子。进一步借助T细胞或巨噬细胞SHP-2条件性敲除小鼠考察SHP-2对肿瘤进展、炎症水平、肿瘤免疫应答的影响以及调控免疫细胞数目、表型、促瘤功能转向的作用方式；运用SHP-2过表达、突变、基因敲低或敲除等方法阐明SHP-2调控肿瘤免疫促瘤转向的分子机制。最后运用化学小分子针对SHP-2进行干预，考察其对肿瘤生长和转移的治疗作用以及对免疫功能促瘤转向的逆转作用。通过上述研究有望发现肿瘤相关性炎症微环境中调控免疫功能转向的重要分子，有助于找到预测和诊断肿瘤的新分子标志或防治肿瘤的新药物靶点。

The host immunity is prone to switch from antitumour to protumour properties in cancer-related inflammation. However, the mechanisms by which a protective tumour-inhibiting immune response can be switched towards a tumour-promoting immune response in tumor microenvironment are not entirely clear. To elucidate the modulatory role of SHP-2 for the balance between antitumour and protumour immune responses, we will firstly analyze the relationship between SHP-2 and tumour development by means of studies on the murine tumour models and clinical tumour samples. Secondly, we will investigate the effects of SHP-2 ablation on tumour progression,inflammatory microenvironment, immune responses and immune cells including the number, phenotypes and antitumour verse protumour function in tumor-bearing T cell-or macrophage-specific SHP-2 knockout mice. Moreover, the signaling mechanisms will be clarified by methods of overexpression, knockdown or knochout of SHP-2. Lastly, we will test whether small molecules which can modulate the expression or function of SHP-2 have the potential to reverse tumour-promoting towards tumour-inhibiting immune responses in the murine tumor models. Taken together, this study will be of importance to identify a molecular switch to modulate the balance between antitumour and protumour immune response, and shed light on the molecular basis of cancer progression. Furthermore, the molecular switch could be not only a novel tumour biomarker for prognosis and diagnosis, but also a new drug target for cancer therapy.