EHD1调控非小细胞肺癌β-catenin/c-Myc通路增强Warburg效应从而抑制NK细胞杀伤活性的研究

NK细胞治疗是肿瘤免疫治疗的重要方法，肿瘤介导NK细胞免疫抑制限制其治疗效果，然而调控机制尚不完全清楚。申请人首次发现下调EHD1的非小细胞肺癌(NSCLC)细胞培养液可增强NK细胞的杀伤活性，EHD1是如何发挥该功能尚无文献报道。前期研究中我们应用基因芯片技术发现EHD1下调可抑制Warburg效应及该效应的上游调控通路β-catenin/c-Myc，并应用质谱进一步发现EHD1与β-catenin通路上游调控分子14-3-3ζ存在相互作用。因此，我们提出了EHD1与14-3-3ζ相互作用激活β-catenin/c-Myc通路促进NSCLC的Warburg效应及乳酸分泌，从而抑制NK细胞杀伤活性的假说。我们拟采用流式等分子生物学技术、动物模型、人体组织标本，研究EHD1介导免疫抑制的分子机制。本课题以新视角探究免疫抑制机制，可能为NSCLC个体化免疫治疗、提高免疫疗效提供新的理论基础。

Natural killer (NK) cells are considered as an important immunotherapeutic agent against malignancies, however the molecular mechanism of cancer cells suppressing the killing effect of NK cells remains largely unclear. We firstly find conditioned media from EHD1 knockdown non-small cell lung cancer (NSCLC) cells inhibits the killing effect of natural killer cells. But its mechanism has not been elucidated. Using microarray, we have discovered that after EHD1 knockdown the Warburg effect and β-catenin/c-Myc signaling pathway, an upstream pathway of Warburg effect, were inhibited in NSCLC cells. By proteomics approach, we found that 14-3-3ζ, an upstream molecular of β-catenin/c-Myc signaling pathway, interacts with EHD1. We hypothesized that EHD1 interacts with 14-3-3ζ to regulate the killing effect of NK cells via enhancing Warburg effect regulated by β-catenin/c-Myc signaling pathway in non-small cell lung cancer. Therefore, we are planning to study the function and mechanism of EHD1 regulating the killing effect of NK cells, by means of molecular biology technology including flow cytometry, xenograft models and patient tissues. This study may provide a new perspective on the mechanism of immune escape and a new theoretical basis for the individualized immunotherapy of NSCLC and the improvement of the efficacy of immunotherapy.