磷酸酶Wip1介导髓系抑制性细胞功能调控肿瘤生长的机制研究

The formation of immunosuppressive microenvironment is a critical factor for tumor immune escape which is in close relation to tumor malignant development and metastasis. Myeloid derived suppressor cells (MDSC) are newly identified innate immune cells which also have potent immunosuppressive function to promote the induction of tumor immune tolerance when compared with classic regulatory T cells. Understanding the mechanisms accounting for the development of MDSC, as well as how to control the inhibitory function of MDSC, may provide benefits for tumor treatment. P53 induced phosphatase 1(Wip1) has been shown to play an important role in the development/function of numerous immune cells, while its role in MDSC has not been elucidated. Our preliminary results showed that deletion of Wip1 in immune cells facilitated the induction of inhibitory immune microenvironmnt possibly due to the development of MDSC as suggested by the enhanced differentiation of MDSC from myeloid progenitor cells with more potent immunosuppressive function after deletion of Wip1. Thus, these results suggested Wip1 may play a critical role in MDSC development/function during tumor progress. With the use of multiple gene knock out mice and relative tumor models, we intend to discover the underlying mechanisms of Wip1 in mastering MDSC development/function, as well as the induction of immunosuppressive microenvironment, which may provide future prospects for improving the efficacy of tumor immunotherapy.

抑制性肿瘤免疫微环境的形成是肿瘤免疫逃逸的重要因素，与肿瘤恶性发展及转移密切相关。髓系抑制性细胞(MDSC)作为具有免疫抑制功能的固有免疫细胞，与经典的调节性T细胞相比，同样是诱导肿瘤免疫耐受的重要细胞群体。深入探索其在肿瘤免疫微环境的发育机制，并有效逆转其在肿瘤免疫中的负向调节功能是近年来肿瘤免疫研究热点。野生型P53诱导的磷酸酶1(Wip1)是近年来新发现的对各群免疫细胞都具有重要调控功能的酶类，然而其对MDSC的功能尚未阐明。我们的前期研究发现免疫细胞内缺失Wip1小鼠肿瘤生长加快，并且Wip1缺失引起骨髓前体细胞向MDSC分化增加，提示Wip1可能在肿瘤进程中调控了MDSC的分化与功能。因此，我们拟应用多种基因敲除小鼠联合小鼠皮下瘤及肺转移等动物模型，探索Wip1调控MDSC的分子机制，有助于揭示肿瘤免疫抑制微环境的形成机制，也为多种肿瘤的免疫治疗提供新思路。

肿瘤免疫抑制微环境的形成是肿瘤免疫逃逸的重要因素，与肿瘤恶性发展及转移密切相关。髓系抑制性细胞作为具有免疫抑制功能的固有免疫细胞，与经典的调节性T细胞相比，同样是诱导肿瘤免疫耐受的重要细胞群体，且是肿瘤免疫抑制微环境得重要组成成分。深入探索其在肿瘤免疫微环境中的发生机制，并有效逆转其在肿瘤免疫中的负向调节功能是近年来肿瘤免疫研究的热点。野生型P53诱导的磷酸酶1(Wip1)是近年来新发现的对各群免疫细胞都具有重要调控功能的磷酸酶，然而其对MDSC的调控作用尚未阐明。我们的研究发现免疫系统缺失Wip1的小鼠肿瘤生长加快，并且Wip1缺失引起骨髓前体细胞向MDSC分化增加，并且Wip1-/-的髓系抑制性细胞抑制功能增强，提示Wip1可能在肿瘤发生过程中调控了MDSC的分化与功能，并且我们的研究发现Wip1主要是通过调控精氨酸酶活性调控髓系抑制性细胞对抗肿瘤免疫的抑制性调控。因此，我们应用多种基因敲除小鼠联合小鼠皮下瘤及等动物模型，探索Wip1调控MDSC的分子机制，有助于揭示肿瘤免疫抑制微环境的形成机制，也为多种肿瘤的免疫治疗提供新思路。