Université de Bordeaux, INSERM, U1312, BRIC, Bordeaux, France.
Université de Limoges, INSERM, U1308, CAPTuR, Limoges, France.
Elife. 2024 Jul 15;13:RP95191. doi: 10.7554/eLife.95191.
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 and , 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.
免疫检查点抑制剂在癌症患者中产生了令人鼓舞的效果。然而，大多数 β-连环蛋白突变的肿瘤被描述为缺乏免疫浸润，对免疫治疗有抗性。致癌 β-连环蛋白影响免疫监视的机制尚不清楚。在这里，我们强调了 β-连环蛋白在调节外泌体途径中的作用，以及在肝癌（HCC）中免疫/癌细胞通讯中的作用。我们表明，突变的 β-连环蛋白抑制了肝癌细胞系和 HCC 患者样本中两种主要的外泌体生物发生因子 和 的表达。通过纳米颗粒跟踪分析和活细胞成像，我们进一步证明了激活的 β-连环蛋白抑制了外泌体的释放。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了免疫细胞浸润的减少。总之，我们的研究结果首次提供了证据，证明致癌 β-连环蛋白在外泌体生物发生中起关键作用。我们的研究为 β-连环蛋白突变对肿瘤微环境重塑的影响提供了新的见解，这可能导致开发新的策略来增强免疫治疗反应。
