PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients.
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.
Shi
Feng
F
Institute of Microbiology, Chinese Academy of Sciences, Beijing, China; Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Shi
Ming
M
Zeng
Zhen
Z
Qi
Rui-Zhao
RZ
Liu
Zhen-Wen
ZW
Zhang
Ji-Yuan
JY
Yang
Yong-Ping
YP
Tien
Po
P
Wang
Fu-Sheng
FS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D060890:B7-H1 Antigen; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology*; D049109:Cell Proliferation; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology; D008103:Liver Cirrhosis / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000473:pathology; D011183:Postoperative Complications; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D055815:Young Adult
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D007371:Interferon-gamma