PDF(Pubmed)
Abstract：
Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of ß-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic ß-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of ß-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated ß-catenin represses expression of SDC4 and RAB27A, two main actors in exosome biogenesis, in both liver cancer cell lines and HCC patient samples. Using nanoparticle tracking analysis and live-cell imaging, we further demonstrated that activated ß-catenin represses exosome release. Then, we demonstrated in 3D spheroid models that activation of β-catenin promotes a decrease in immune cell infiltration through a defect in exosome secretion. Taken together, our results provide the first evidence that oncogenic ß-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of ß-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response.
摘要：
免疫检查点抑制剂在癌症患者中产生了令人鼓舞的结果。然而,大部分β-catenin突变的肿瘤被描述为缺乏免疫浸润和免疫疗法耐药.致癌β-catenin影响免疫监视的机制尚不清楚。在这里，我们强调β-catenin参与外泌体途径的调节，通过延伸,在肝细胞癌（HCC）的免疫/癌细胞通讯中。我们发现突变的β-catenin抑制SDC4和RAB27A的表达，外来体生物发生的两个主要参与者，在肝癌细胞系和HCC患者样本中。使用纳米粒子跟踪分析和活细胞成像，我们进一步证明了活化的β-catenin抑制了外来体的释放。然后，我们在3D球体模型中证明,β-连环蛋白的激活通过外泌体分泌缺陷促进免疫细胞浸润的减少.一起来看,我们的研究结果提供了第一个证据,证明致癌β-catenin在外泌体生物发生中起关键作用.我们的研究为β-catenin突变对肿瘤微环境重塑的影响提供了新的见解。这可能导致提高免疫治疗反应的新策略的发展。
