肿瘤相关巨噬细胞 (TAMs)是肿瘤微环境的重要组成部分，抑制TAMs的M2型极化是极具应用前景的抗肿瘤转移新策略。新近发现轴突导向分子SEMA6A参与免疫反应、抑制肿瘤进展。但SEMA6A是否通过重塑炎症微环境调控肿瘤转移不清楚。我们前期探索分析发现：结直肠癌组织中SEMA6A的表达水平下降，与肿瘤发生远处转移及患者生存期呈负相关，SEMA6A过表达的结直肠癌细胞肝脏转移显著抑制，M2型TAMs浸润减少，并下调细胞因子PLGF的合成。据此假设：SEMA6A与结直肠癌细胞表面PlexinA4受体结合，通过下调PLGF合成分泌，介导TAMs由M2型向M1型极化，通过增强抗肿瘤免疫效应，抑制结直肠癌肝脏转移。本申请将阐明SEMA6A通过重塑炎症微环境抑制结直肠癌肝脏转移，揭示其调节TAMs表型极化的分子机制。本研究将为开发基于抑制M2型极化的全新抗肿瘤转移药物及肿瘤免疫治疗提供重要的科学依据。

Tumor associated macrophages (TAMs) are a large component of the tumor microenvironment, which promote tumor cells invasion and metastasis, and they are related to malignant degree and poor prognosis. TAMs depolarization from M2 phenotype is considered to be a promising anti-metastasis strategy. Recent studies have been shown that SEMA6A, the axon guidance molecule is involved in immune response and inhibits tumor progression. However, whether SEMA6A regulates tumor metastasis via affecting inflammatory microenvironment is unclear. Our preliminary studies and database analysis suggested that a significant downregulation in SEMA6A expression in colorectal carcinoma tissues as compared with normal specimens, and loss of SEMA6A expression was negatively associated with distant metastasis and poor prognosis of colorectal carcinoma patients. SEMA6A overexpression colorectal carcinoma cells showed a significant decrease in liver metastatic foci and a less M2-TAMs infiltration when implanted in WT mice with downregulation of tumor cells-produced placenta growth factor (PLGF). Thus, we hypothesized that SEMA6A might block PLGF production via the receptor PlexinA4 of colorectal carcinoma cells, contributing to skewing TAMs polarization away from the M2- to a tumor-inhibiting M1-like phenotype, leading to suppressing liver metastasis of tumor cells. The goals of this project are: 1) to determine its role in liver metastasis of colorectal carcinoma cells, 2) to elucidate how SEMA6A inhibits tumor metastasis via regulating TAMs polarization. The proposed studies will provide new knowledge regarding mechanisms of TAMs polarization, thus addressing a fundamental issue for new approaches in antitumor drugs and tumor immunotherapy based on polarizing TAMs away from the M2 phenotype.