PD-1⁺ TIGIT⁺ CD8⁺ T cells are associated with pathogenesis and progression of patients with hepatitis B virus-related hepatocellular carcinoma

Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) is usually considered an inflammation-related cancer associated with chronic inflammation triggered by exposure to HBV and tumor antigens. T-cell exhaustion is implicated in immunosuppression of chronic infections and tumors. Although immunotherapies that enhance immune responses by targeting programmed cell death-1(PD-1)/PD-L1 are being applied to malignancies, these treatments have shown limited response rates, suggesting that additional inhibitory receptors are also involved in T-cell exhaustion and tumor outcome. Here, we analyzed peripheral blood samples and found that coexpression of PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) was significantly upregulated on CD4⁺ and CD8⁺ T cells from patients with HBV-HCC compared with those from patients with chronic HBV or HBV-liver cirrhosis. Additionally, PD-1⁺ TIGIT⁺ CD8⁺ T-cell populations were elevated in patients with advanced stage and progressed HBV-HCC. Importantly, PD-1⁺ TIGIT⁺ CD8⁺ T-cell populations were negatively correlated with overall survival rate and progression-free survival rates. Moreover, we showed that PD-1⁺ TIGIT⁺ CD8⁺ T cells exhibit features of exhausted T cells, as manifested by excessive activation, high expression of other inhibitory receptors, high susceptibility to apoptosis, decreased capacity for cytokine secretion, and patterns of transcription factor expression consistent with exhaustion. In conclusion, PD-1⁺ TIGIT⁺ CD8⁺ T-cell populations are associated with accelerated disease progression and poor outcomes in HBV-HCC, which might not only have important clinical implications for prognosis but also provide a rationale for new targets in immunotherapy.