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

## TL;DR

This study shows how alpha-fetoprotein helps liver cancer cells avoid detection by immune cells, offering new insights into cancer immune evasion.

## Contribution

The paper reveals a novel mechanism by which AFP promotes immune escape in HCC via MICA/B cleavage and MMP9 activation.

## Key findings

- AFP reduces membrane MICA/B levels in HCC cells by upregulating MMP9 through the PI3K/AKT pathway.
- High AFP levels suppress NK-92 cell activity and cytokine release, aiding HCC immune evasion.
- Interfering with AFP reverses its immunosuppressive effects on NK-92 cells.

## Abstract

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.