Liver kinase B1 in exosomes inhibits immune checkpoint programmed death ligand 1 and metastatic progression of intrahepatic cholangiocarcinoma.

Abstract

The increasing morbidity and high mortality of intrahepatic cholangiocarcinoma (ICC) has led to the urgent need for new diagnostics and therapeutics. Liver kinase B1 (LKB1) exerts a tumor suppressor role in multiple malignances, while its regulatory role in exosomes secreted by ICC cells is obscure. In the present study, exosomes were extracted from cell culture supernatants of RBE and HCCC-9810 ICC cells as well as plasma of patients with ICC by ultracentrifugation and the morphology of exosomes was identified by transmission electron microscopy. Notably, compared with that of intracellular LKB1, the protein level of exosomal LKB1 was decreased. Silencing intracellular LKB1 increased the protein levels of programmed death ligand 1 (PD-L1), Slug and phosphorylated-AKT in exosomes, accompanied by decreased expression levels of exosomal LKB1. Exosomes with lower protein levels of LKB1 promoted the expression of the immune checkpoint PD-L1, malignant phenotypes of ICC cells in vitro, and cancer metastasis in vivo. Moreover, the low level of exosomal LKB1 in plasma was tightly associated with the poor prognosis of patients with ICC. Collectively, exosomal LKB1 inhibits the immune checkpoint PD-L1 and metastasis of ICC cells. These findings may provide new methods for the diagnosis and immune therapy of ICC.