PMN-MDSC（不均一核髓系抑制性细胞）是肿瘤免疫耐受的重要参与者，但缺乏特异性标记。新近报道LOX-1是其特异性标记，我们前期研究（Nat Med 2018共一；Immunology 2018通讯；Kid Int 2017通讯）发现LOX-1+PMN-MDSC促进肝癌疾病进展，内质网应激是其关键特征，但其诱导机制尚不明确。进一步筛选发现肝癌外泌体是诱导LOX-1+PMN-MDSC的关键物质，而其通过转运血管紧张素转化酶（ACE）激活中性粒细胞内肾素血管紧张素系统（RAS）、导致氧化应激可能是其机制。因而我们提出“肝癌外泌体通过转运ACE激活中性粒细胞内RAS、诱导氧化应激，促进中性粒细胞向LOX-1+PMN-MDSC转化”的科学假说。本项目将利用肝癌患者外周血、组织芯片样本、基因干预小鼠、小鼠肝癌模型等手段验证此假说，揭示调控肝癌PMN-MDSC的新机制，为设计免疫靶向治疗提供理论依据

Polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) is an critical participant in tumor immune tolerance, but it is lack of specific markers. It has been found recently that LOX-1 is a specific marker of PMN-MDSC. Our previous studies （Nat Med 2018 co-first author；Immunology 2018 corresponding author; Kid Int 2017 corresponding author）and found that LOX-1+PMN-MDSC promoted hepatocellular carcinoma (HCC) development and endoplasmic reticulum stress was the key feature in the mechanism. However, the cause of endoplasmic reticulum stress is still unclear. After screening, we found that the exosome of hepatocellular carcinoma was the only substance that can induce LOX-1+PMN-MDSC.It activated renin-angiotensin system (RAS) in neutrophils by transporting angiotensin converting enzyme (ACE), which might lead to oxidative stress. This might be the latent mechanism. Therefore, we propose a scientific hypothesis that exosome from hepatocellular carcinoma activate RAS and induce oxidative stress in neutrophils by transporting ACE, which promotes the transformation of neutrophils to LOX-1+PMN-MDSC. This project will validate this hypothesis by using liver cancer clinical blood samples, tissue array, gene intervention in mice and mouse liver cancer model, reveal the new mechanism of regulating PMN-MDSC in tumors, and provide theoretical basis for the design of targeted immunotherapy.