Alpha‐Fetoprotein Stimulates Cleavage of Membranal <scp>MICA</scp> /B on Liver Cancer Cell Lead to Escape Immune Surveillance of Natural Killer Cells

Hepatocellular carcinoma (HCC) could escape immune surveillance. Alpha-fetoprotein (AFP) serves as a significant biomarker for HCC; however, its influence on HCC immune surveillance remains elusive. RNA-Seq data of HCC were obtained from TCGA and GEO databases for the expression of AFP, MICA/B, and related genes. Immunohistochemistry for protein detection in tissues; the expression of target proteins was detected by Western blotting; membrane protein expression and cytotoxicity assessment were analysed by flow cytometry; protein localization was observed by immunofluorescence, cytokine levels were detected by ELISA; mRNA quantification was analysed by qRT-PCR, cell proliferation was measured by CCK-8, animal experiments were applied to observe immune response, and cytotoxicity assays were used to evaluate the killing effect of natural killer-92 (NK-92) cells. Results indicated that in both databases and patient tissues, AFP and MICA/B were highly expressed in the HCC tissues. AFP inhibits the membrane level of MICA/B in HCC cells and promotes the shedding of MICA/B by upregulating MMP9 expression via activation of the PI3K/AKT signalling pathway. Furthermore, AFP suppressed NK-92 cells from attacking HCC cells and restricted the release of cytokines by NK-92 cells, whereas interference with AFP had opposite effects. This finding indicated that AFP stimulated the cleavage of membrane MICA/B in HCC cells, increased the content of soluble MICA/B, and blocked the interaction between MICA/B and NKG2D, which may be involved in the upregulation of MMP9 expression via activation of the PI3K/AKT signalling pathway. These effects inhibited the activation of NK-92 cells, causing HCC cells to escape attack by NK-92 cells.