IDO/AhR轴调节中性粒细胞促进肝癌进展的机制研究

Hepatocellular carcinoma(HCC) is a high morbidity and motality malignant tumor,and the treatment of advanced HCC is a big problem worldwide. We found that the count of peripheral blood neutrophils is an independent risk factor of survival for HCC patients,and protumor genes as NOS2 and MMP9 were higher expressed in the neutrophils of HCC patiens.However,it is unknown that who controls these protumor genes.Tumor metabolism plays an important role in the regulation of tumor immune microenviroment,especially the suppression of anti-tumor effect of T cell by the enhancement of amino acid metabolism.This study focused on the regulatory effect of amino acid metabolism on neutrophils.We hypothesised that high expression of IDO in HCC increased kynurenine by tryptophan metabolism,which further recruitment neutrophils to tumor microenviroment and active the AhR in neutrophils to behave the protumor characteristics.This study is to verify the regulatory effect of IDO/AhR axis to neutrophils by in vivo and in vitro experiments and clinical samples,and to provide a new target and theoretical basis for the treatment of advanced HCC.

肝细胞癌是高发病率和高死亡率的恶性肿瘤，晚期肝癌的治疗是目前肝癌治疗领域的难题。我们前期研究发现，肝癌患者外周血中性粒细胞计数升高是影响生存的独立危险因素，并且高表达NOS2、MMP9等促癌特征。但是，中性粒细胞促癌特征转变的调控机制仍然不明。肿瘤代谢对肿瘤免疫微环境起着调控作用，尤其是氨基酸代谢的增强对T细胞的抑制作用在恶性肿瘤的进展中发挥了重要作用。本研究着眼于氨基酸代谢对中性粒细胞促癌特征的调控，提出肝癌细胞通过高表达IDO使色氨酸代谢产物犬尿氨酸（Kyn）增多、Kyn进一步活化了中性粒细胞AhR受体使其在肿瘤部位募集并表现出促癌特征的假说，拟通过体内、体外实验及临床样本的验证，明确IDO/AhR轴对中性粒细胞促进肝癌进展的调控机制，为晚期肝癌的免疫治疗提供新的靶点和理论基础。

肿瘤代谢对肿瘤免疫微环境起着调控作用，尤其是氨基酸代谢的增强在恶性肿瘤的进展中发挥了重要作用。本课题以外周血中性粒细胞为研究对象，分析其与肝癌患者预后的关系，并从肝癌增殖、迁移、侵袭、血管生成及CD8+T细胞功能改变等多角度研究，通过构建稳定过表达IDO人肝癌细胞株、构建小鼠肝脏原位移植瘤模型等研究方法，证实中性粒细胞是影响肝癌患者生存期的独立危险因素，肝癌患者中性粒细胞表达MMP9升高并促进肿瘤进展，IDO 通过上调中性粒细胞 MMP9 表达促进肿瘤进展。本研究证实了色氨酸代谢的关键酶IDO对中性粒细胞促癌作用的调控机制，为靶向中性粒细胞的肝癌联合治疗提供了理论基础。