TIGIT expression induces NKT-like cell hypofunction in hepatocellular carcinoma patients with high HBV load

Abstract Persistent hepatitis B virus (HBV) infection can induce chronic hepatitis B and liver cirrhosis and gradually progress to hepatocellular carcinoma (HCC). Particularly, a high serum HBV DNA level is a major risk factor for the development of HCC. CD3⁺CD56⁺ NKT-like cells play a pivotal role in human antiviral defense and tumor immune surveillance. Nevertheless, the mechanism underlying the immune status of NKT-like cells in HCC patients with high HBV DNA level remains to be elucidated. In this study, we demonstrated that peripheral blood NKT-like cells from HCC patients with high HBV DNA level (high-HBV HCC patients, HBV DNA > 10 4 IU/mL) displayed hypofunction, characterized by upregulated expression of the inhibitory receptor TIGIT and impaired secretion of antiviral effector cytokines. Elevated TIGIT expression on NKT-like cells is positively correlated with HBV DNA level in HCC patients. Moreover, the immune activity of TIGIT⁺ NKT-like cells was significantly lower than that of the TIGIT⁻ subset. Meanwhile, we found that compared to HCC patients with low HBV DNA level (low-HBV HCC patients), the expression of CD155 (the ligand for TIGIT) on plasmacytoid dendritic cells (pDCs) was markedly upregulated in high-HBV HCC patients. Co-culture assay of NKT-like cells and pDCs showed that TIGIT blockade restored the effector function of NKT-like cells of HCC patients upon HBcAg stimulation. Taken together, our results indicate that the TIGIT pathway mediates hypofunction of NKT-like cells in high-HBV HCC patients, providing a rationale for developing novel immune checkpoint for HCC patients with high HBV load.