肝细胞癌肿瘤微环境中白介素-37调控肿瘤相关巨噬细胞的作用机制研究

肿瘤细胞通过募集免疫细胞并与之相互作用构成复杂的肿瘤微环境，以此逃逸机体免疫监视。肿瘤相关巨噬细胞（TAM）是肿瘤微环境的主要组成部分，在肿瘤发生发展过程中发挥重要作用，与包括肝细胞癌（HCC）在内多种肿瘤的不良预后密切相关。IL-37是新发现的IL-1细胞因子家族成员，能够抑制固有免疫应答，申请者在J. Immunol.发表报道对其在自身免疫性皮肤病银屑病中的免疫调节功能进行了深入阐述，但迄今为止该分子在肿瘤发病机制中的作用尚不明确。课题前期研究表明IL-37高表达于HCC肿瘤组织的TAM，且与患者术后生存期呈负相关，IL-37可能是关联肿瘤与免疫的重要分子，藉由TAM的免疫抑制和促血管生成机制促进肿瘤的生长转移。我们将从分子、细胞及IL-37转基因小鼠整体水平深入研究其对TAM的免疫调节作用。申请者有较好的肿瘤研究基础，希望能够对肿瘤的免疫病理机制深入探讨，为肿瘤免疫治疗提供新思路。

Tumor cells can recruit and interact with immune cells to form a immune inhibitory tumor microenvironment in the body of patient for evading immune surveillance and promoting tumor cell growth and metastasis. As the major part of the tumor microenvironment, tumor associated macrophage (TAM) plays a crucial role in the process of tumorigenesis, progression, and metastasis, and is closely related to the poor prognosis of a variety of malignant tumors, including hepatocellular carcinoma (HCC). Interleukin-37 (IL-37), newest member of IL-1 family, is foudamental inhibitor of innate immunity. We have reported the immune regulation role of IL-37 in psoriasis （chronic cutaneous autoimmune didorder）on J.Immunol. The results of our preliminary studies suggested IL-37 was highly expressed in HCC tumor tissues, and its expression was negatively correlated with the survival of HCC patients; we further found that IL-37 was mainly expressed in tumor infiltrating macrophages, but the precise mechanism is still unknown. We thus suppose that IL-37 may be a new key regulator on the commnication of tumor growth and inflammation, and promote the tumor growth and metastasis by suppressing the immune system and promoting angiogenesis through TAM. Several technological strategies, such as molecular biology, cell culture, transgenic mice models, gene chips and bioinformatics technology would be used to study the function and molecular mechanism of IL-37 in tumor microenvironment. Our previous researches have laid solid foundation in tumor immunotherapy. The implementation of this project will deepen our understanding on the pathogenesis of malignant tumor, but also provide some new ideas for the development of new clinical diagnosis markers and tumor treatment strategies.