FAK/NF-κB/CD276信号通路在结直肠癌免疫逃逸中的作用及分子机制研究

Tumor immunotherapy, as a novel biotherapy method, has been widely used in the treatment of various cancers, but it is not sensitive in colorectal cancer. Therefore, it is urgent to find a new immunotherapy target of colorectal cancer. Recent study demonstrats that FAK plays an important role in tumor immune regulation. Our previous data shows that the expression and activity of FAK are enhanced in colorectal cancer, and its genomic is amplificated. Subsequently, we find immune checkpoint CD276 is positively correlated with FAK expression and can be regulated by FAK. Further study show that CD276 expression in colorectal cancer is increased and its high expression is associated with the poor prognosis of colorectal cancer patients. Bioinformatics analysis demonstrates that CD276 promoter posses several potential binding sites of NF-κB1, and inhibition of NF-κB1 could down-regulate CD276 protein expression in colon cancer cells. In addition, we also find that the FAK gene amplification and high expression in colorectal cancer is positively correlated with the activation of NF-κB1. Moverover, inhibiting FAK can reduce the activation of NF-κB1, indicating FAK play a crucial role in the activation of NF-κB1. In this study we will further clarify the regulatory mechanism of CD276 by FAK through serious experiments and elucidate the role of CD276 in colorectal cancer immune evasion, which will provide us a new therapy target for colorectal cancer immunotherapy.

肿瘤免疫治疗作为一种新兴的生物治疗方法已广泛应用于多种肿瘤治疗,并取瞩目的成果，但在结直肠癌中并不敏感，因此亟需寻找新的肠癌免疫治疗靶点。最新研究表明，FAK在肿瘤免疫调节中发挥重要作用。我们前期发现结直肠癌中FAK表达及活化增强且存在基因组扩增，而免疫检查点CD276与FAK呈正相关并受FAK调节。进一步研究发现，肠癌组织中CD276表达升高且其高表达与肠癌患者的不良预后相关。生物信息学分析显示CD276启动子上存在NF-κB1潜在结合位点，抑制NF-κB1活性能下调肠癌细胞中CD276的蛋白表达。此外我们还发现，肠癌中FAK基因扩增及表达升高与NF-κB1的活化相关，抑制FAK能削减NF-κB1的活化，提示FAK参与NF-κB1的活化。本研究拟通过体内外实验明确FAK调控CD276的机制，并阐明CD276在结直肠癌免疫逃逸中功能机制，为结直肠癌的免疫治疗提供新靶点和理论。

肿瘤免疫治疗作为一种新兴的生物治疗方法已广泛应用于多种肿瘤治疗并取瞩目的成果，但在结直肠癌中并不敏感，因此亟需寻找新的肠癌免疫治疗靶点。最新研究表明，FAK在肿瘤免疫调节中发挥重要作用。本研究发现结直肠癌中FAK表达及活化增强且存在基因组扩增，肠癌细胞中敲减FAK1的表达能够抑制免疫检查点CD276的表达，且CD276在肠癌组织中显著高表达。CD276蛋白可通过抑制T细胞的增殖及肿瘤中CD8+T的浸润，促进肿瘤细胞免疫逃逸增强肿瘤生长，靶向CD276的CAR-T细胞具有较强抗肿瘤活性，本研究将为结直肠癌的免疫治疗提供新靶点和理论基础。