肿瘤相关巨噬细胞(TAM)是肿瘤微环境中重要的免疫抑制细胞，但其形成及功能机制尚未完全清楚。我们已结题项目证实:肿瘤细胞能释放分泌型自噬小体(TRAP)并诱导B细胞成为具有免疫抑制功能的Breg细胞。近期实验发现:TRAP也能诱导单核细胞极化成为具有M2型特性的巨噬细胞(上调CD206/IL-10/PD-L1表达)，其机制有待深入研究。. 本项目拟研究:①TRAP诱导M2型巨噬细胞极化的分子机制(通过何种配体/受体、活化途径诱导巨噬细胞极化?缺氧/缺营养条件来源TRAP是否促进极化?);②TRAP诱导M2型巨噬细胞的免疫调节作用及其机制(PD-L1/IL-10?接触/非接触?对免疫细胞/肿瘤细胞分别具有哪些调节作用?);③肿瘤微环境TRAP与M2型巨噬细胞极化的关系(动物模型和临床研究)。阐明TRAP与巨噬细胞极化的关系将为研究TAM的形成及功能机制提出新的思路。

Our previous studies have demonstrated the tumor-released secretory autophagosoms (TRAP) could induce B cells to differentiate into IL-10-producing regulatory B cells via the HMBG1-TLR2-MyD88-NF-κB pathway, which could potently inhibit T cell responses in IL-10-depedent manner. Our recent data showed that TRAPs could induce M2 polarization of macrophage, however, the involved mechanisms have not been studied so far. .In this study, we will investigate that: (A) the molecular mechanism of M2 polarization of macrophage induced by TRAPs, involved macrophage recognition, DAMPs on TRAP and signal transduction pathway of macrophage polarization. (B) the molecular mechanism of immunosuppressive functions TRAPs-induced M2 macrophage on antitumor immune responses or/and tumor cell growth invasion, and metastasis. (C) the correlation between functional polarization of macrophage and secretory autophagosoms released tumor cells in the tumor microenvironment..It is hoped that seeking effect of TRAPs on M2 macrophage would improve the understanding about development and differentiation of tumor-associated macrophages (TAMs) in the tumor microenvironment.