酪氨酸磷酸酶和酪氨酸激酶的动态平衡是影响肿瘤发生发展的核心和关键。申请人前期研究发现，SSH1在ICC中特异性高表达，一方面直接促进ICC细胞增殖、侵袭和转移，另一方面驱动多种免疫活性介质释放，招募中性粒细胞浸润发挥促癌作用。我们提出“SSH1直接促进ICC恶性进展并间接通过CXCL7/8-CXCR2生物轴招募中性粒细胞浸润发挥促癌作用，是ICC临床治疗新靶点”的研究假说，通过体内外模型和相关机制研究，拟阐明ICC细胞和微环境中性粒细胞间存在以SSH1为关键调控点的“交叉对话”，进而引发肿瘤恶性进展和免疫抑制反应，并尝试靶向SSH1治疗ICC，为基于SSH1的分子靶向治疗提供可靠的理论指导和实验依据。本项目重点从微环境角度，以中性粒细胞为代表，研究免疫微环境对ICC发生发展的影响、SSH1在其中的关键调控作用，拓展对免疫微环境和ICC相互作用的认识，为ICC的靶向治疗提供新思路。

Protein tyrosine phosphorylation, maintained by the dynamic balance between the activities of protein tyrosine phosphate and protein tyrosine kinase, plays a key role in the tumorigenesis and progression. Our previous research indicated that slingshot 1 (SSH1), a non-receptor tyrosine phosphate, was specifically highly expressed in intrahepatic cholangiocarcinoma (ICC), promoting cancer progression by enhancing proliferation, migration and invasion of ICC cells. Besides, SSH1 was found to be implicated in the production of multiple chemokines, modulating neutrophil cell recruitment and finally contributing to cancer progression. We hypothesize that SSH1 directly promote ICC progression and indirectly aggravate by recruiting neutrophil cell infiltration via CXCL7/8-CXCR2 axis. SSH1 might be a novel therapeutic target of ICC and there is a potential cross-talk between cancer cells and neutrophil cells, in which SSH1 should be a key factor that contributes to cascade reaction of neutrophil cell-mediated immunosuppression and cancer aggressiveness. In this study, we emphatically determine to investigate the essential role of SSH1 in neutrophil cell recruitment, find the intricate mechanisms of how SSH1 modulate the immunosuppressive effect, with the aim of extending the understanding of microenvironment in tumor progression and providing potential therapeutic target for ICC.