TREM-1作为炎症微环境“检查点”促肝癌进展的机制及治疗价值研究

Hepatocellular carcinoma is a typical inflammation-related cancer, and the inflammatory environment inside the tumor has a pivotal role in disease progression as well as drug resistance. Our previous study has shown that triggering receptor expressed on myeloid cells 1 (TREM-1) was specifically expressed in HCC cells and inflammatory cells in the tumor microenvironment. It is reasonable to hypothesize TREM-1 might be a tumor-promoting inflammation checkpoint. And our object of the project was to find the intricate mechanism of how TREM-1 controls the tumor-promoting inflammatory cascades and to study its potential as a therapeutic target for HCC. Besides, inhibition of inflammation inside the microenvironment by blocking TREM-1 could attenuate inflammation-mediated tumor proliferation and metastasis, which is of great importance for HCC therapeutic strategy and for providing a better prognosis for the patients.

肝癌是典型的炎症相关肿瘤，炎症微环境对肝癌的发生、发展和治疗抵抗有重要影响。申请人前期研究发现新型炎症触发受体TREM-1在肝癌细胞和微环境炎症细胞中特异性高表达，可促进肝癌细胞分泌一系列炎症因子、趋化因子及生长因子，表达水平高者预后差。本项目从肿瘤微环境中炎症角度出发，首次提出“TREM-1是肝癌促癌炎症微环境形成的检查点（Inflammation checkpoint）”的研究假说，通过体内外模型及相关机制研究，拟阐明肝癌细胞和微环境中炎症细胞之间存在以TREM-1 为“炎症检查点”的交叉对话，进而激活肝癌微环境中促癌炎症反应的级联信号和正反馈环路，导致肝癌进展和治疗抵抗。靶向TREM-1可阻断其介导的炎症放大作用，减轻肿瘤微环境的炎症反应，抑制典型的炎症相关肝癌的生长、侵袭及转移，缓解炎症微环境对肝癌耐药性的影响，为临床基于“炎症检查点”的靶向治疗提供可靠的理论指导和实验依据。

阐明TREM-1对肝癌微环境“炎症检查点”TREM-1分子对肿瘤生物学特性的影响和分子机制。TREM-1是新型炎症激发受体。本项目主要探究肝癌微环境“炎症检查点”TREM-1分子的功能。主要结果如下：1）发现TREM-1表达于肝癌微环境中的肿瘤相关性单核/巨噬细胞上，并且TREM-1的表达与肝癌的复发与转移正相关；2）对肝癌组织、癌旁组织及外周血的TREM-1+/-巨噬细胞转录组测序，明确TREM-1分子的作用和机制，富集分析发现TREM-1参与炎症反应调节及免疫相关通路；3）体外实验研究发现TREM-1+巨噬细胞促进肿瘤生长可能机制；4）PDX模型发现TREM-1能够增强肝癌细胞对索拉非尼的敏感性，提高疗效。上述结果为解释TREM-1促进肝癌进展提供了理论解释，并且对临床治疗提供参考意义。本项目资助已发表研究论文3篇，其中The Journal of Pathology杂志1篇，Journal of Surgical Oncology杂志1篇，Clinical Cancer Research杂志1篇。