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Cancer Immunology, Immunotherapy

, Volume 68, Issue 12, pp 2041–2054 | Cite as

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

  • Xiaoli Liu
  • Mengge Li
  • Xinhui Wang
  • Zhibo Dang
  • Yuyong Jiang
  • Xianbo Wang
  • Yaxian KongEmail author
  • Zhiyun YangEmail author
Original Article

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.

Keywords

TIGIT Programmed cell death-1 Prognosis HCC Coexpression 

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

Notes

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.

Author 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.

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).

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).

Informed consent

Each patient and healthy donors signed an informed consent. They all agreed to use their specimens and clinical information for this research.

Supplementary material

262_2019_2426_MOESM1_ESM.pdf (8.6 mb)
Supplementary material 1 (PDF 8804 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Xiaoli Liu
    • 1
  • Mengge Li
    • 2
  • Xinhui Wang
    • 1
  • Zhibo Dang
    • 1
  • Yuyong Jiang
    • 1
  • Xianbo Wang
    • 1
  • Yaxian Kong
    • 3
    Email author
  • Zhiyun Yang
    • 1
    Email author
  1. 1.Center for Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Department of hepatobiliary spleen and stomachHenan Province of TCMZhengzhouPeople’s Republic of China
  3. 3.Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan HospitalCapital Medical UniversityBeijingPeople’s Republic of China

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