内质网应激诱导的exosomes释放对肿瘤微环境的调控及其在肝癌免疫逃逸中的作用

Endoplasmic reticulum stress (ERS) plays crucial role in the immune escape of liver cancer. However, how tumor cell under ERS affecting immune cells in the tumor microenvironment and then leading to immune eascape remain unclear. Exosomes as a meidation communication among different cell types is becoming a hot topic in basic and clinical research area. Until now, there are no evidence showing the relationship between ERS and exosomes. Our previous studies found that ERS stimulated tumor cell to secrect exosomes affecting immune cell function. Moreover, we found 18 miRNAs including miRNA-22 in hepatoma cells significantly changed after ERS stimulation. Base on these finding, we propose the hypothesis that ERS-mediated exosomes releasing from hepatoma carcinoma cells may induce immune tolerance in the tumor microenvironment. To test this hypothesis, we will first compare the discrepancy of ERS-related exosomes-miRNAs. Then we will screen out the immune related specific miRNAs. Last we will confirm the effects of these specific exosomes-miRNAs on immune cell fuctions with cell and animal models. We anticipate that results from the proposed studies will provide new evidences for the crosstalk between tumor cells and immune cells via ERS-exosomes pathway. Our future finding will also give experiments data supporting for the searching for new, safe and effective antitumor drug targets.

内质网应激（ERS）在肝癌免疫逃逸中起重要作用，但肿瘤细胞在ERS状态下，如何作用于其微环境中免疫细胞，进而引起免疫逃避的机制尚不清楚。Exosomes在细胞间信息传递的媒介作用是目前研究热点。ERS与exosomes的关系尚未见报道，我们前期发现肝癌细胞ERS后分泌的exosomes可影响免疫细胞功能，同时发现肝癌细胞ERS后miRNA-22等18条miRNAs的表达发生显著变化，由此推断ERS可能通过调控exosomes-miRNAs释放介导肿瘤微环境免疫耐受。本课题拟首先比较肝癌细胞ERS相关exosomes-miRNAs差异，然后筛选免疫功能相关特异miRNAs，进而在细胞和整体水平上验证肝癌细胞ERS相关exosomes对免疫细胞功能的影响。本研究将丰富和加深ERS-exosomes途径参与肿瘤细胞-免疫细胞之间相互作用的机制的认识，为寻找安全、有效的抗肿瘤新靶点提供实验依据。

内质网应激（ERS）在肝癌免疫逃逸中起重要作用，但肿瘤细胞在ERS状态下，如何作用于其微环境中免疫细胞，进而引起免疫逃避的机制尚不清楚。Exosomes在细胞间信息传递的媒介作用是目前研究热点。ERS与exosomes的关系尚未见报道，我们发现肝癌细胞ERS后分泌的exosomes可影响巨噬细胞功能，同时发现肝癌细胞ERS后miRNA-23a-3p等的表达发生显著变化， 内质网应激的肝癌细胞释放的exosome通过传递miRNA-23a-3p抑制PTEN表达，从而激活PI3K-AKT-PD-L1通路上调巨噬细胞PD-L1表达。本研究将丰富和加深ERS-exosomes途径参与肿瘤细胞-免疫细胞之间相互作用的机制的认识，为寻找安全、有效的抗肿瘤新靶点提供实验依据。