Cholangiocarcinoma derived exosomes attenuate the anti-tumor functions of NK cells

Natural killer (NK) cells play critical roles in anti-tumor immunity however are always frustrated in some solid tumors. Tumor derived exosomes usually facilitate tumor progression via regulating immune cells functions. The effects of CCA (cholangiocarcinoma)-derived exosomes (CCA-Exos) on NK cells functions remain unclear. The objective of this study was to investigate whether and how the CCA-Exos affect the NK cells anti-tumor activity. Immunohistochemical staining displayed that the infiltration of NK cells decreased obviously in tumor lesions compared with the paracancerous tissues. Exosomes were isolated from human primary cholangiocarcinoma cell lines (RBE cells), patients and healthy people serum. Flow cytometry assay revealed that both exosomes from patient serum and RBE cells induced apoptosis of NK-92 cells. BCL-2 and BCL-XL were downregulated by RBE cells exosomes in both of transcriptional and protein levels. Besides, exosomes-treated NK-92 cells lost the normal clustered growing as well as the lower expression of adhesion molecules of CD11a, CD18 and CD54 and decreased production of IFN-γ and granzyme B. The killing activity of NK-92 cells against target cells was also attenuated by exosomes. NK cells in the peripheral blood of CCA patients also showed significantly lower cytotoxicity and expression of adhesion molecules compared to NK cells in the peripheral blood of healthy people. However, the proliferation of NK-92 cells was not affected by exosomes. This study suggests that cholangiocarcinoma may escape the immune surveillance by suppressing the NK cell functions from multiple aspects through exosomes.