LAIR1-mediated resistance of hepatocellular carcinoma cells to T cells through a GSK-3β/β-catenin/MYC/PD-L1 pathway

Background: An increasing number of studies have reported the involvement of oncogenes in the regulation of the immune system. LAIR1 is an immunosuppressive molecule and its role in immune-related diseases has been mainly reported. To date, it is unclear whether LAIR1 in tumor cells is involved in immune regulation. Therefore, the aim of this study was to investigate the role of LAIR1 in the immune microenvironment of hepatocellular carcinoma (HCC) to seek the novel therapeutic discoveries.

Methods: Tumor Immune Dysfunction and Exclusion database was used to predict the response of LAIR1 expression to immune checkpoint blockade. CD8⁺ T cells were co-cultured with HCC cells, and the killing efficiency of leukocytes on HCC cells was detected by flow cytometry. Flow cytometry was also used to detect the expression of inhibitory receptors. In addition, Western blot, immunofluorescence, and nucleus/cytoplasm fractionation experiments were performed to explore the molecular mechanisms by which LAIR1 created a suppressive tumor microenvironment.

Results: LAIR1 expression in HCC was associated with worse immune prognosis and T-cell dysfunction. HCC cells overexpressing LAIR1 co-cultured with CD8⁺ T cells induced exhaustion of latter. Mechanism studies indicated that LAIR1 in HCC cells up-regulated the phosphorylation of β-catenin by inducing the phosphorylation of GSK-3β, leading to the impairment of the expression and the nuclear localization signal of β-catenin. Low β-catenin expression and nuclear localization signal inhibited MYC-mediated PD-L1 expression. Therefore, PD-L1 up-regulated by LAIR1 caused the exhaustion of infiltrating CD8⁺ T cells in HCC, which aggravated the malignant progression of HCC.

Conclusion: LAIR1 increased PD-L1 expression through the GSK-3β/β-catenin/MYC/PD-L1 pathway and promoted immune evasion of HCC cells. Targeted inhibition of LAIR1 helped to enhance the immune killing effect of CD8⁺ T cells in HCC.

Hepatocellular carcinoma; LAIR1; MYC; PD-L1; T-cell killing.