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

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Abstract

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.

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Abbreviations

AFP:

α-Fetoprotein

ALB:

Albumin

ALT:

Alanine aminotransferase

AUROC:

Area under the receiver-operating characteristic

BCLC:

Barcelona clinic liver cancer

BTLA:

B- and T-lymphocyte attenuator

CHB:

Chronic hepatitis B virus infection

CTLA-4:

Cytotoxic T-lymphocyte antigen 4

Eomes:

Eomesodermin

FITC:

Fluorescein isothiocyanate

HBeAg:

Hepatitis B e antigen

HBV-HCC:

Hepatitis B virus-associated hepatocellular carcinoma

HCV:

Hepatitis C virus

HIV:

Human immunodeficiency virus

HR:

Hazard ratio

IFN-γ:

Interferon gamma

LAG-3:

Lymphocyte-activation gene 3

LC:

Liver cirrhosis

MELD:

Model for end-stage liver disease

NLR:

Neutrophil–lymphocyte ratio

NK:

Natural killer cells

OS:

Overall survival

PBMC:

Peripheral blood mononuclear cell

PD-1:

Programmed cell death-1

PD-L1:

Programmed death-ligand 1

PFS:

Progression-free survival

TBIL:

Total bilirubin

TCM:

Central memory T cells

TEM:

Effector memory T cells

TEMRA:

Terminally differentiated effector T cells

TIGIT:

T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain

TILs:

Tumor-infiltrating lymphocytes

TIM-3:

T-cell immunoglobulin domain and mucin domain 3

TNF-α:

Tumor necrosis factor

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Acknowledgements

We would like to thank Lihua Yu and Dongdong Zhou for their assistance with the follow-up of survival information in HBV-HCC patients.

Funding

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).

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Authors and Affiliations

  1. Center for Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Beijing, 100015, People’s Republic of China

    Xiaoli Liu, Xinhui Wang, Zhibo Dang, Yuyong Jiang, Xianbo Wang & Zhiyun Yang

  2. Department of hepatobiliary spleen and stomach, Henan Province of TCM, No. 6 Dongfeng Road, Zhengzhou, 450002, Henan Province, People’s Republic of China

    Mengge Li

  3. Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Beijing, 100015, People’s Republic of China

    Yaxian Kong

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  1. Xiaoli Liu
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Contributions

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.

Corresponding authors

Correspondence to Yaxian Kong or Zhiyun Yang.

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The authors declare that they have no conflict of interests.

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The study was approved by the ethics committee of Beijing Ditan Hospital, Capital Medical University (2016-1-28).

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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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Liu, X., Li, M., Wang, X. et al. PD-1+ TIGIT+ CD8+ T cells are associated with pathogenesis and progression of patients with hepatitis B virus-related hepatocellular carcinoma. Cancer Immunol Immunother 68, 2041–2054 (2019). https://doi.org/10.1007/s00262-019-02426-5

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