中性粒细胞(PMN)对肿瘤免疫及肿瘤生长转移的调节作用愈受重视，但机制尚未明了。.前期研究显示：肿瘤细胞能释放分泌型自噬小体(TRAP)并极化Mϕ成为具有免疫抑制功能的M2型细胞(PD-L1↑)。 近期发现：PMN能快速高效吞噬TRAP并调节多种功能分子表达(如趋化类CCR7↑/CCL2↑/CXCR2↓；粘附类ICAM-1↑)、抑制T细胞增殖及促进肿瘤细胞转移，其机制值得深入研究。.本项目拟探讨：①TRAP活化PMN及其分子机制(由何种配/受体、信号分子调节何种功能分子表达？)；②TRAP活化PMN抑制T细胞应答与效应及其分子机制(何种分子介导活化PMN趋向脾脏/淋巴结并抑制T细胞应答？)；③促进肿瘤细胞生长转移及其机制(何种分子介导活化PMN与肿瘤/内皮细胞粘附？)；④临床相关性分析(临床资料/自噬水平/PMN及其功能分子)，旨在阐明TRAP活化PMN调节肿瘤免疫及肿瘤生长转移的新机制。

Our previous studies have demonstrated that tumor cell-released autophagosomes (TRAPs) not only induced B cell to differentiate into IL-10-producing regulatory B cell via the HMGB1-TLR2-MyD88-NF-κB pathway, which potently inhibited T cell responses in IL-10-dependent manner, but also induced macrophages to differentiate into IL-10＋PD-L1highCD206high M2-like macrophages via the TLR4-MyD88-p38-Stat3 pathway, which potently suppressed T cell responses in PD-L1-dependent manner. Our recent data showed that neutrophils that have phagocytized TRAPs inhibited the proliferation of T cells in a cell contact- and ROS-dependent manner and promoted the growth, invasion and metastasis of tumor cells, however, the mechanisms involved have not been elucidated so far..In this study, we will further investigate: (A) The molecular mechanism of neutrophil polarization induced by TRAPs, including neutrophil recognition, DAMPs on TRAP, signal transduction pathway of neutrophil polarization and production of immunomodulatory molecules. (B) The molecular mechanism of immunosuppressive functions of TRAP-induced neutrophil on antitumor immune T cell responses, growth, invasion and metastasis of tumor cells, polarization and chemotaxis of macrophages. (C) The correlation between tumor-associated neutrophils (TAN) and secretory autophagosomes released by tumor cells in the tumor microenvironment..We anticipate that elucidating the effect of TRAPs on neutrophils would improve the understanding about development and immunosuppressive functions of tumor-associated neutrophils in the tumor microenvironment.