ESE3表达缺失促进胰腺癌MDSC聚集及免疫逃逸的机制研究

Tumor immune escape plays a risk role affecting the prognosis and chemotherapy effectiveness in patients of pancreatic cancer. Our previous study revealed that ESE3 acts as a tumor suppressor gene in pancreatic cancer, which inhibits pancreatic cancer metastasis .The results have been published in Cancer Research. On this basis we found that the expression of ESE3 may also associated with immune escape, the downregulation of ESE3 may promote the MDSC accumulation which suppress T-cell function and trigger immune escape.According to our RT-PCR date,GM-CSF was screened out that plays an important role in MDSC expansion . Thus, we aim to clarify the effect of ESE3 on MDSC function and immune escape from animal model level and cellular level,to elucidate the mechanism of ESE3 on MDSC expansion and on inhibiting immune escape.Finally, decitabine, which increases ESE3 expression, was used to investigate the effect on increasing sensitivity of gemcitabine by releasing the immune escape,In conclusion,our study will be the first time to reveal the impact of ESE3 on immune escape in pancreatic cancer , but also provide a novel target for therapy of pancreatic cancer.

肿瘤免疫逃逸是影响胰腺癌患者预后和化疗有效性的重要危险因素。本课题组首次发现并报道ESE3在胰腺癌中作为抑癌基因抑制肿瘤细胞的侵袭转移，部分成果已发表在Cancer Research上，在此基础上，我们在组织学水平发现ESE3的表达缺失可能导致胰腺癌免疫逃逸的发生，ESE3降表达后促进肿瘤组织中MDSC的聚集，并介导免疫逃逸，通过RT-PCR实验分析筛选出与ESE3相关性最大的免疫抑制分子GM-CSF，本课题拟在前期工作基础上利用动物模型和体外共培养实验从动物水平和细胞水平进一步明确ESE3对MDSC功能的影响，揭示ESE3的缺失导致胰腺癌免疫逃逸的具体分子机制。最后利用增加ESE3表达的药物地西他滨，探究其通过解除免疫逃逸状态增加吉西他滨敏感性的作用。本项目的研究不仅有助于阐明ESE3抑制胰腺癌免疫逃逸的分子机制，而且能为胰腺癌治疗提供新思路和新靶点。

胰腺癌是恶性程度非常高的消化系统肿瘤，由于胰腺癌细胞处于复杂的免疫抑制微环境中，使免疫治疗在胰腺癌中受到较大程度的限制，同时也是胰腺癌患者对传统的化疗方案产生耐药性的重要因素。本课题组在高通量筛选的基础上首次报道ESE3作为抑癌基因在胰腺癌中发挥作用。通过体内动物实验，病理组织层次验证了ESE3在胰腺癌中的表达水平与组织中浸润的MDSC的含量成负相关，并且与CD8+T细胞的含量呈正相关。通过体外细胞共培养技术证实了ESE3能够通过抑制GM-CSF的转录调控从而抑制MDSC的诱导转变，从而增加CD8+T细胞的含量及功能。通过染色质免疫共沉淀实验与双荧光素酶实验证实了ESE3作为转录因子通过与GM-CSF的启动子区结合，从而抑制GM-CSF的转录调控。以此为理论基础做了临床转化，在小鼠模型中证实通过过表达ESE3增加抗PD-1的疗效。本课题通过证实上述通路，为胰腺癌发生免疫逃逸提供了理论基础，并为胰腺癌的临床转化提供新的分子靶点。