胃癌细胞源外泌体microRNA介导巨噬细胞CXCL8分泌促进免疫逃逸的机制研究

胃癌（GC）细胞通过微环境中巨噬细胞（mø）激活CXCL8/PD-L1通路逃避T细胞免疫监视。但GC细胞如何逃避NK细胞的免疫监视，目前尚未清楚。MICB是介导NK细胞功能的关键检查点。前期研究发现GC细胞可刺激巨噬细胞高表达CXCL8，预实验发现GC细胞源外泌体也有此功能，而且CXCL8可上调GC细胞MICB的表达。因此我们提出GC细胞源外泌体microRNA通过抑制HDAC上调CXCL8在mø的表达，CXCL8通过GC细胞受体CXCR1/2激活PI3K/AKT通路，上调MICB的表达，促进其逃避NK细胞监视的假说。本项目采用高通量测序、类器官模型等技术，阐明GC细胞通过外泌体的microRNA促进mø分泌CXCL8，正反馈促进自身逃避NK细胞免疫监视的机制，为胃癌免疫治疗提供新思路。

Gastric cancer (GC) cells escape T-cell immune surveillance through macrophages derived CXCL8/PD-L1 signaling. The mechanism of GC cells escaping NK-cell surveillance remains elusive. MICB is a critical check point for NK cells. Our previous study found that GC cells can promote the high expression of CXCL8 in macrophages, and preliminary results showed that GC cells-derived exosomes have similar effect and CXCL8 can upregulate the expression of MICB in GC cells. Therefore, we hypothesize that GC cells-derived exosomal microRNA induces the secretion of CXCL8 in macrophages through decreasing HDAC expression and the high level of CXCL8 upregulates MICB expression in GC cells through activating CXCR1/2-PI3K/AKT pathway, thus promoting GC development through escaping NK-cell immune surveillance. In this project, we will examine which microRNA in GC cells-derived exosome can upregulate CXCL8 in macrophage by high throughput sequencing and Luciferase reporter assay. In addition, we will explore whether CXCL8 can upregulate the expression of MICB in GC cells to escape immune surveillance by activating CXCR1/2-PI3K/AKT pathway through in vitro and in vivo experiments and organoid technology. These results will provide novel insights into understanding the interactions on immune escape between GC cells and macrophages and shed light to new immunotherapy for GC.