C-MET扩增通过调控乙酰辅酶A羧化酶重塑EGFR突变型肺癌免疫微环境的机制研究

研究表明，EGFR突变型肺癌因肿瘤内部缺少淋巴细胞浸润，因此对抗PD-1免疫治疗效果不佳。我们发现，EGFR突变继发C-MET扩增的肺癌患者，接受免疫治疗有效，但具体机制尚不清楚。前期研究显示：C-MET扩增与肿瘤浸润淋巴细胞增加有关。我们通过对TCGA肺癌数据库，临床标本及细胞模型进行分析，发现C-MET扩增可能通过抑制乙酰辅酶A羧化酶（ACC）激活下游IFN-α/β信号通路，诱导趋化因子产生从而增加肿瘤浸润淋巴细胞的数目。因此我们提出，C-MET扩增可能通过ACC激活IFN-α/β信号通路重塑EGFR突变型肺癌免疫微环境的科学假说。本研究拟通过构建细胞模型及小鼠模型等体内外实验，旨在：1）系统阐述C-MET扩增影响淋巴细胞浸润重塑肿瘤微环境的分子机制；2）ACC抑制剂联合PD1抑制剂治疗EGFR突变型肺癌患者的疗效。为提高肺癌患者免疫治疗疗效提供新思路。

Previous studies have shown that lung cancer with EGFR mutant is poor responded to anti-PD-1 immunotherapy because of the lack of lymphocyte infiltration in the tumor;Immunotherapy was found to be effective in lung cancer patients with C-MET amplification and EGFR mutation, but the potential mechanism remains unclear.Our previous studies showed that C-MET amplification was significantly associated with the increase of tumor infiltrating lymphocytes.Through the analysis of TCGA lung cancer database, clinical specimens and cell models, we found that C-MET amplification may activate the downstream IFN-α/β signaling pathways and induce the production of chemokines by inhibiting Acetyl-CoA carboxylase (ACC) so as to increase the number of tumor infiltrating lymphocytes.Therefore, we propose the scientific hypothesis that C-MET amplification may reshape the immune microenvironment of lung cancer with EGFR mutant by activating the IFN-α/β signaling pathway through ACC.This study aims to achieve the following objectives by constructing cell models and mouse models in vivo and in vitro experiments.First, The molecular mechanism of the effect of c-MET amplification on lymphocyte infiltration and tumor microenvironment . Second, the efficacy of ACC inhibitor combined with PD-1 inhibitor in the treatment of lung cancer patients with EGFR mutant which can provide a new idea for improving the efficacy of immunotherapy in lung cancer patients.