MDSC调控非小细胞肺癌EGFR-TKI获得性耐药的分子机制研究

EGFR-TKI获得性耐药是非小细胞肺癌（NSCLC）治疗中丞待解决的重大难题。我们前期在EGFR-TKI敏感与耐药性NSCLC“肿瘤免疫双人源化”小鼠及临床患者病灶中发现，髓源性抑制细胞（MDSC）在耐药后浸润增多，抑制其功能可明显提高疗效、逆转耐药。进一步预实验显示耐药病灶MDSC既能降低NSCLC细胞EGFR-TKI敏感性，又能抑制T淋巴细胞增殖，其机制可能与增强NSCLC细胞线粒体氧化磷酸化（OXPHOS）以及高表达吲哚胺2,3-双加氧酶1（IDO1）有关。本项目拟从两个方面阐明NSCLC肿瘤微环境中MDSC调控EGFR-TKI获得性耐药的分子机制：⑴通过增强NSCLC细胞线粒体OXPHOS影响其EGFR-TKI敏感性；⑵通过高表达IDO1来调节局部免疫抑制性微环境。本研究将进一步解析NSCLC中EGFR-TKI获得性耐药的产生机制，为该现象的临床防治提供新的生物标志物与干预靶点。

EGFR-TKI is the first-line treatment for non-small cell lung cancer (NSCLC), but the acquired resistance is a major obstacle for the successful treatment. Our previous work has identified that the infiltration of myeloid-derived suppressor cell (MDSC) is significantly increased in the tumor tissues with acquired resistance to EGFR-TKI, whether in NSCLC patient-derived xenograft models in humanized mice, or in clinical NSCLC patients. We have also found that specific inhibition of the MDSC activity can increase the efficiency of EGFR-TKI. Further experiments showed that the MDSC from EGFR-TKI resistant tumor tissues could downregulate the sensitivity of NSCLC cells to EGFR-TKI, and also, could inhibit the proliferation of T cells. The mechanisms may be associated with the enhancement of mitochondrial oxidative phosphorylation (OXPHOS), as well as the upregulated expression of indoleamine 2,3-dioxygenase 1(IDO1). In the present study, firstly we will explore the underlying mechanisms of MDSC in mitochondrial OXPHOS and EGFR-TKI sensitivity regulation in NSCLC cells. Secondly, we will clarify the effect of MDSC on tumor immunosuppressive microenvironment through IDO1, as well as its influence on the efficacy of EGFR-TKI. Finally, we will verify the clinical significance of MDSC related molecules in acquired resistance to EGFR-TKI in NSCLC patients. This project will provide new biomarkers and potential intervention targets for acquired resistance to EGFR-TKI in NSCLC.