Repression of exosome secretion by mutated β-catenin contributes to immune escape in hepatocellular carcinoma

Dantzer, C.; Vache, J.; Brunel, A.; Mahouche, I.; Raymond, A.-A.; Dupuy, J.-W.; Petrel, M.; Bioulac-Sage, P.; Perrais, D.; Dugot-Senant, N.; Verdier-Sage, M.; Bessette, B.; Billottet, C.; Moreau, V.

doi:10.1101/2023.10.24.563805

bioRxiv · 10.1101/2023.10.24.563805

Repression of exosome secretion by mutated β-catenin contributes to immune escape in hepatocellular carcinoma

Dantzer, C.·Vache, J.·Brunel, A.·Mahouche, I.·Raymond, A.-A.·Dupuy, J.-W.·Petrel, M.·Bioulac-Sage, P.·Perrais, D.·Dugot-Senant, N.·Verdier-Sage, M.·Bessette, B.·Billottet, C.·Moreau, V.

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Abstract

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.

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Dantzer, C., Vache, J., Brunel, A., Mahouche, I., Raymond, A.-A., Dupuy, J.-W., Petrel, M., Bioulac-Sage, P., Perrais, D., Dugot-Senant, N., Verdier-Sage, M., Bessette, B., Billottet, C., Moreau, V.. 2023-10-27. Repression of exosome secretion by mutated β-catenin contributes to immune escape in hepatocellular carcinoma. https://doi.org/10.1101/2023.10.24.563805

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