吞噬受体SLAMF7通过激活HS1促进巨噬细胞抗肿瘤免疫的机制研究

巨噬细胞在肿瘤微环境中发挥重要的免疫调节作用，对巨噬细胞功能和表型的干预已成为肿瘤免疫疗法的研究热点。巨噬细胞CD47-SIRPa通路（“别吃我”信号）协助肿瘤免疫逃逸，是肿瘤免疫疗法的新靶点，但Mφ的“吃我”信号及机制鲜有报道。我们前期研究发现Mφ上SLAMF7/Mac-1复合物活化“吃我”信号，激活抗肿瘤免疫(Nature,2017)，但其中确切的分子机制还知之甚少，限制了免疫疗法的应用。我们最近发现细胞骨架运动对吞噬活性不可或缺，SLAMF7能够通过激活HS1，促进细胞骨架运动，进而启动吞噬功能。以此为基础，本项目拟结合体外实验和多种基因敲除小鼠模型，进一步探索SLAMF7通过HS1调节细胞骨架运动和吞噬作用的分子机制；探讨其对抗肿瘤免疫应答及免疫治疗的影响。该研究将有助于阐明巨噬细胞吞噬肿瘤的机制，并为探讨通过调控Mφ吞噬功能来开发新型肿瘤免疫治疗策略提供理论基础和临床转化依据。

Macrophage plays critical immune regulation function in tumor microenvironment. Re-programming of macrophage function is a novel direction for cancer immunotherapy. The CD47-SIRPa phagocytosis checkpoint pathway (‘Don’t eat me’ signal) induces tumor immune escape, thus can be a potential target for cancer immunotherapy. But the mechanism of ‘Eat me’ signal is barely known. Our previous work revealed the phagocytic receptor SLAMF7/Mac-1 complex-mediated signaling pathway activates macrophage phagocytosis, but the molecular mechanisms are poorly understood. Our preliminary data showed that the cytoskeleton polarization is critical for phagocytosis and SLAMF7 recruits the cytoskeleton protein HS1 to initiate cytoskeleton polarization, leading to phagocytosis activation. Based on these findings, this project will study the function of cytoskeleton polarization during phagocytosis, and explore the molecular mechanism of the activation of cytoskeleton polarization and tumor phagocytosis by SLAMF7 through interacting with HS1. Furthermore, we will reveal the functional mechanism of SLAMF7 and HS1 in macrophage-mediated cancer immunotherapy. In summary, this study will extend our understanding of macrophage phagocytosis and provide a theoretical basis and novel targets for the establishment of new cancer immunotherapy strategies.