抑癌基因ESE3下调诱导胰腺癌免疫逃逸的机制研究

Pancreatic cancer is characterized by high malignancy with poor prognosis, in which tumor immune escape plays a critical role during the cancer development. It was reported that immune escape in pancreatic cancer may be related to inactivation of certain immune suppressor genes. We recently found that tumor suppressor gene ESE3 could positively regulate E-Cadherin so that induce the EMT-driven tumor invasion and metastasis. Interestingly, ESE3 downregulation may also promote the Treg function which will trigger the immune escape. Thus, we are hypothesizing that ESE3 probably induce the Treg-stimulated immune escape via the immune suppressor TGFβ1 according to our RNA-seq data. Firstly, we will propose to use plenty of in vitro and in vivo assays to detect if the change of ESE3 will influence the Treg function. Secondly, molecular functional assays will be done to elucidate how ESE3 regulates the TGFβ1 to impact the immune escape. Finally, we will introduce the novel TGFβ inhibitor, RER which was firstly reported by the applicant, to study if blocking the immune escape will sensitize the gemcitabine chemotherapy, further inhibiting the tumor invasion. Our study, for the first time, will illustrate the mechanism of how ESE3 impacts the immune escape in pancreatic cancer and make immune escape inhibition a possible treatment for pancreatic cancer.

肿瘤的免疫逃逸是胰腺癌恶性程度高及治疗效果差的重要原因。课题组前期研究结果显示，胰腺癌免疫逃逸可能与抑癌基因ESE3的下调有关；降表达ESE3可能促进免疫细胞Treg功能的激活，介导免疫逃逸；通过二代测序结果分析发现ESE3可能上调免疫抑制因子TGFβ1。因此课题组提出假设：ESE3可能通过上调TGFβ1的转录表达促进Treg介导的胰腺癌免疫逃逸。为验证这一假设，本项目拟首先通过体内外实验论证肿瘤细胞ESE3的表达变化对Treg功能的影响；其次通过ChIP和Co-IP等分子功能学实验阐明ESE3上调TGFβ1从而影响免疫逃逸的具体机制；最后利用申请人设计的新型TGFβ抑制剂“RER”封闭肿瘤微环境的TGFβ1，研究RER通过抑制胰腺癌局部免疫逃逸达到增敏吉西他滨化疗效果的作用。本课题的研究将为胰腺癌的免疫逃逸机制和化疗增敏提供新的理论支撑。

肿瘤的免疫逃逸是胰腺癌恶性程度高及治疗效果差的重要原因。课题组前期研究结果显示，胰腺癌免疫逃逸可能与抑癌基因ESE3的下调有关；降表达ESE3可能促进免疫细胞Treg功能的激活，介导免疫逃逸；通过二代测序结果分析发现ESE3可能上调免疫抑制因子TGFβ1。因此课题组提出假设：ESE3可能通过上调TGFβ1的转录表达促进Treg介导的胰腺癌免疫逃逸。课题组利用细胞分子生物学技术重点研究了胰腺癌肿瘤细胞ESE3 对免疫抑制细胞Treg 功能的影响，阐明胰腺癌细胞ESE3 调控免疫抑制因子TGFβ1 的分子机制并最终探究不同表达ESE3 的胰腺癌动物模型对免疫抑制治疗的有效性。通过一系列研究已证实ESE3通过直接调控转录翻译上调TGFβ1的表达机制并阐明ESE3的确实对免疫微环境的负调控作用，最终利用动物试验证实高表达ESE3可以抑制胰腺癌的免疫逃逸，使荷瘤小鼠从抗PD-1治疗中获益。 该研究较全面揭示了胰腺癌中抑癌基因ESE3的缺失通过上调TGFβ1表达及其功能调控胰腺癌免疫微环境，可能是胰腺癌免疫治疗增敏的靶点，可能成为一个较有前景的提示抗PD1治疗效果的预测指标。