ABCG1介导肿瘤相关巨噬细胞极化在非小细胞肺癌侵袭转移的作用机制

Globally, lung cancer ranks the most frequently diagnosed cancer and the major cause of cancer-related mortality. The incidence of lung cancer in our country keeps rising in recent years. Human immune-checkpoint-inhibitor antibodies inhibit the PD-1 receptor or PD-L1, which improves antitumor immunity. In the latest progress of cancer immunology, tumor-associated macrophage was proved to play a key role in the tumor microenvironment. Tumor-associated macrophages could polarize towards an inflammatory ‘M1’ or a pro-tumor ‘M2’ state, depending on their environmental stimuli. ABCG1 effluxes excess cholesterol to high-density lipoprotein particles for reverse cholesterol transport, which is an essential path to the elimination of intercellular cholesterol. It is reported that Abcg1 knockout mice exhibited massive accumulation of neutral lipids and phospholipids in macrophages which correlate to ‘M1’ state. In the present study, we aim to investigate the ability of ABCG1 mediates the tumor-associated macrophage polarization in the mechanism of non-small cell lung cancer invasion and migration, which may provide new insights in cancer biology and evidence for future clinical practice.

全球肺癌居于癌症发病率以及病死率首位，我国近年呈上升趋势。以免疫共刺激因子PD-1/PD-L1靶向治疗为代表，非小细胞肺癌免疫治疗取得较大进展。肿瘤免疫相关机制中肿瘤微环境浸润的巨噬细胞是其关键环节之一。巨噬细胞可分为M1型激活免疫应答发挥抗肿瘤作用， M2型诱导免疫耐受有促肿瘤作用。既往研究表明巨噬细胞向M2型转化与肿瘤免疫逃逸促恶性进展相关。ABCG1为跨膜蛋白调控胆固醇外流，该基因缺乏引起细胞内胆固醇堆积促进巨噬细胞向M1型转换。本项目拟研究ABCG1介导巨噬细胞极化在非小细胞肺癌侵袭转移的作用机制，体内及体外实验结合，采用慢病毒载体过表达及沉默策略技术、基因敲除动物模型、临床样本中评价其与非小细胞肺癌恶性进展的相关性。并予调控细胞内胆固醇水平，阐明ABCG1、胆固醇水平、巨噬细胞极化在肿瘤免疫的网络机制，调控该机制对PD-1抑制剂敏感性的影响，为临床转换研究奠定理论基础。

肿瘤免疫相关机制中肿瘤微环境浸润的巨噬细胞是其关键环节之一。巨噬细胞可分为M1型激活免疫应答发挥抗肿瘤作用， M2型诱导免疫耐受有促肿瘤作用。既往研究表明巨噬细胞向M2型转化与肿瘤免疫逃逸促恶性进展相关。前期研究发现ABCG1与肺癌预后相关，并参与巨噬细胞极化调控。本项目研究ABCG1介导巨噬细胞极化在非小细胞肺癌侵袭转移的作用机制，通过分析临床样本中巨噬细胞极化状态及ABCG1表达水平，发现肺癌中ABCG1均有不同程度表达，中强阳性表达占分析样本中的51%。采用单核巨噬细胞与肿瘤细胞共培养，采用慢病毒载体过表达及沉默策略技术，临床样本表达等评价其与非小细胞肺癌恶性进展的相关性，M2型巨噬细胞中ABCG1表达升高，M1型巨噬细胞中降低，通过沉默ABCG1可以是巨噬细胞向M1型转化，沉默ABCG1共培养肿瘤细胞后，肿瘤细胞的凋亡增加增殖降低。ABCG1通过调节巨噬细胞极化影响肿瘤表型。