PMN-MDSCs通过内质网应激-脂代谢途径活化介导肝癌TACE与TKI治疗耐受的机制研究

经导管动脉化疗栓塞术（TACE）联合酪氨酸激酶抑制剂（TKI）治疗肝癌对比TACE的多项临床研究呈阴性，提示存在限制因素。前期研究发现：TACE与TKI治疗可导致肝癌患者中性粒细胞（PMN）增多；体内实验中仑伐替尼可上调CXCL5招募PMN向瘤内浸润，且表型往具有促瘤作用的多叶核髓源抑制细胞（PMN-MDSC）转化；PMN-MDSC主要依赖于内质网应激-脂代谢途径活化发挥促瘤作用，小鼠肝癌模型中仑伐替尼联合选择性靶向PMN-MDSC的脂代谢途径抑制剂Lipofermata能产生协同效应。因此我们假设TACE与仑伐替尼可激活PMN内质网应激-脂代谢通路转化为PMN-MDSC介导治疗耐受。本项目将深入研究肝癌TACE与TKI治疗后PMN-MDSC内质网应激-脂代谢途径活化的具体分子机制；系统评价TACE、仑伐替尼及Lipofermata联合（序贯）治疗的效果及毒副作用，为临床转化提供理论基础。

The negative outcomes in various clinical trials of Transcatheter arterial chemoembolization(TACE) plus tyrosine kinase inhibitor (TKI) versus TACE alone to treat hepatocellular carcinoma indicated limitations among them. Preliminary investigations have found that combination therapy with TACE and TKI contribute to the enhanced accumulation of neutrophil(PMN) in patients with hepatocellular carcinoma; Lenvatinib can up-regulate CXCL5 to promote intratumoral neutrophils infiltration in vivo, and the phenotype was transformed to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) which had tumor-promoting effects; The pro-tumorigenic capacity of PMN-MDSC predominantly dependent on the activation of endoplasmic reticulum stress-lipid metabolism pathway, and combination therapy with Lenvatinib and Lipofermata(a inhibitor of lipid metabolism which highly selective targeting of PMN-MDSC) in tumor-bearing mice, showed a good synergistic effect. Therefore, we hypothesize that TACE and lenvatinib can activate the endoplasmic reticulum stress-lipid metabolism pathway in PMN which then can be transformed into PMN-MDSCs, mediating the resistance of combined treatment of TACE and TKI.This research project will provide an in-depth insight into the specific molecular mechanism of the combination treatment-resistant in HCC which mediated by PMN-MDSCs through endoplasmic reticulum stress-lipid metabolism pathway, and systematically evaluate the efficacy and side effects of the combined (sequential) therapy of TACE, LEN and Lipofermata, so as to provide the theoretical foundations for clinical translation studies.