Emerging role of oncogenic β-catenin in exosome biogenesis as a driver of immune escape in hepatocellular carcinoma

Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of beta-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic beta-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of beta-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated beta-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 beta-catenin represses exosome release. Then, we demonstrated in 3D spheroid models that activation of beta-catenin promotes a decrease in immune cell infiltration through a defect in exosome secretion. Taken together, our results provide the first evidence that oncogenic beta-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of beta-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response.