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.
KeywordsTIGIT Programmed cell death-1 Prognosis HCC Coexpression
Area under the receiver-operating characteristic
Barcelona clinic liver cancer
B- and T-lymphocyte attenuator
Chronic hepatitis B virus infection
Cytotoxic T-lymphocyte antigen 4
Hepatitis B e antigen
Hepatitis B virus-associated hepatocellular carcinoma
Hepatitis C virus
Human immunodeficiency virus
Lymphocyte-activation gene 3
Model for end-stage liver disease
Natural killer cells
Peripheral blood mononuclear cell
Programmed cell death-1
Programmed death-ligand 1
Central memory T cells
Effector memory T cells
Terminally differentiated effector T cells
T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain
T-cell immunoglobulin domain and mucin domain 3
Tumor necrosis factor
We would like to thank Lihua Yu and Dongdong Zhou for their assistance with the follow-up of survival information in HBV-HCC patients.
ZY and YK designed the study; XL and YK performed experiments and wrote the manuscript; ML, XW, and ZD provided patient material and performed experiments; YJ and XW were responsible for the interpretation of data and revision of the manuscript.
This work was supported by Application of Clinical Features of Capital City of Science and Technology Commission (No. Z171100001017082); the Fund for Beijing Science & Technology Development of TCM (No. JJ2016-14); the Fund of Special research of TCM in Capital City (17ZY02), the National Key Sci-Tech Special Project of China (No. 2018ZX10302207).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interests.
Ethics approval and consent standards
The study was approved by the ethics committee of Beijing Ditan Hospital, Capital Medical University (2016-1-28).
Each patient and healthy donors signed an informed consent. They all agreed to use their specimens and clinical information for this research.
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