PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients

Int J Cancer. 2011 Feb 15;128(4):887-96. doi: 10.1002/ijc.25397.


Programmed death 1 (PD-1) and its ligand (PD-L1) play pivotal roles in regulating host immune responses. However, the inhibitory effects of this pathway on the function of cytotoxic CD8(+) T lymphocytes, the main effector cells in hepatocellular carcinoma (HCC) patients, are not well defined. In this study, we characterized circulating and intratumor PD-1/PD-L1 expression and analyzed their association with disease progression in a cohort of hepatitis B virus-infected patients, including 56 with HCC, 20 with liver cirrhosis (LC) and 20 healthy controls (HC). The frequency of circulating PD-1(+) CD8(+) T cells increased with disease progression from LC to HCC patients versus HC. Furthermore, tumor-infiltrating effector CD8(+) T cells showed a drastic increase in PD-1 expression. These increases in circulating and intratumor PD-1(+) CD8(+) T cells could predict poorer disease progression and postoperative recurrence. Immunohistochemical staining showed that PD-L1 expressing hepatoma cells and apoptotic infiltrating CD8(+) T cells were both enriched in tumor sections. In vitro, CD8(+) T cells induced PD-L1 expression on hepatoma cells in an IFN-γ-dependent manner, which in turn promoted CD8(+) T cells apoptosis, and blocking PD-L1 reversed this effect. Therefore, this study extends our knowledge of the role of the PD-1/PD-L1 pathway in tumor evasion and provides evidence for a new therapeutic target in HCC patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / metabolism*
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis*
  • B7-H1 Antigen
  • Blotting, Western
  • CD8-Positive T-Lymphocytes / physiology*
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology*
  • Cell Proliferation
  • Disease Progression
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Immunoenzyme Techniques
  • Interferon-gamma / metabolism
  • Liver / immunology
  • Liver / pathology
  • Liver Cirrhosis / immunology
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / immunology
  • Neoplasm Recurrence, Local / pathology
  • Postoperative Complications*
  • Programmed Cell Death 1 Receptor
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation
  • Young Adult


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • RNA, Messenger
  • Interferon-gamma