Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma
Open accessAbstract
The interaction between T cell immunoglobulin- and mucin-domain-containing molecule (Tim-3) expressed on T helper 1 (Th1) cells, and its ligand, galectin-9, negatively regulates Th1-mediated immune responses. However, it is poorly understood if and how the Tim-3/galectin-9 signaling pathway is involved in immune escape in patients with hepatocellular carcinoma (HCC). Here we studied the expression, function, and regulation of the Tim-3/galectin-9 pathway in patients with hepatitis B virus (HBV)-associated HCC. We detected different levels of galectin-9 expression on antigen-presenting cell (APC) subsets including Kupffer cells (KCs), myeloid dendritic cells (DCs), and plasmacytoid DCs in HCC. The highest galectin-9 expression was on KCs in HCC islets, not in the adjacent tissues. Furthermore, Tim-3 expression was increased on CD4+ and CD8+ T cells in HCC as compared to the adjacent tissues, and Tim-3+ T cells were replicative senescent and expressed surface and genetic markers for senescence. Interestingly, tumor-infiltrating T-cell-derived interferon (IFN)-γ stimulated the expression of galectin-9 on APCs in the HCC microenvironment. Immunofluorescence staining revealed a colocalization of Tim-3+ T cells and galectin-9+ KCs in HCC. Functional studies demonstrated that blockade of the Tim-3/galectin-9 signaling pathway importantly increased the functionality of tumor-infiltrating Tim-3+ T cells as shown by increased T-cell proliferation and effector cytokine production. Finally, we show that the numbers of Tim-3+ tumor-infiltrating cells were negatively associated with patient survival. Conclusion : Our work demonstrates that the Tim-3/galectin-9 signaling pathway mediates T-cell senescence in HBV-associated HCC. The data suggest that this pathway could be an immunotherapeutic target in patients with HBV-associated HCC. (Hepatology 2012)
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High expression of Tim-3, CD57, and KLRG-1, in addition to low CD28, is thought to be associated with T cell senescence.
“In addition to low expression of CD28, high expression of Tim-3, CD57, killer cell lectin-like receptor subfamily G, member 1 (KLRG-1) are thought to be associated with T cell senescence [40,60–64](Fig. 2).”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [40]
HCC-associated Tim-3+ T cells express reduced CD28, suggesting they may be at an early senescence stage.
“HCC-associated Tim-3+T cells expressed reduced CD28, suggesting that these cells may be early senescence stage [40].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [40]
In patients with hepatocellular carcinoma, PD-1 and Tim-3 expression minimally overlaps in tumor-infiltrating T cells.
“in patients with HCC, the expression of PD-1 and Tim-3 is minimally overlapping in tumor infiltrating T cells.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [40]
Blockade of Tim-3 and PD-1 rescues effector functions, shown by cell cycle progression and acquired effector cytokine expression and cytotoxicity.
“blockade of these surface molecules allows rescue of their effector functions as shown by cell cycle progression and acquired effector cytokine expression and cytotoxicity [40,43,44].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [40]
Human HCC-associated T cells highly express Tim-3 and cyclin-dependent kinase inhibitors, interact with galectin-9+ myeloid APCs, and fail to enter the cell cycle.
“human HCC- associated T cells highly express Tim-3 and cyclin dependent kinase inhibitors, and interact with galectin-9+myeloid APCs. These cells fail to enter the cell cycle [40].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [40]
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Research works printed but not linked: 2
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Self-citation
- Authors
- Li, H., Wu, K., Tao, K., Chen, L., Zheng, Q., Lu, X., Liu, J., Shi, L., Liu, C., Wang, G., & Zou, W.
- Affiliations
- Wuhan Union Hospital (CN)
- Wuhan Blood Center (CN)
- University of Michigan (US)
- Corresponding author
- Wang, Guobin
- Zou, Weiping
- ORCID
- Venue
- Hepatology
- Published
- 2012-10
- Volume
- 56
- Issue
- 4
- Pages
- 1342-1351
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2036574174
- Cited by
- 496
- References
- 56
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 44 · 2023: 38 · 2022: 37 · 2021: 55 · 2020: 61 · 2019: 40 · 2018: 39 · 2017: 33 · 2016: 28 · 2015: 30 · 2014: 17 · 2013: 21 · 2012: 3
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Funders
- Changjiang Scholar Program of Chinese Ministry of Education
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Galectins and Cancer Biology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- T cell senescence, T cell dysfunction, tumor-infiltrating T cells, Kupffer cells, antigen-presenting cells, Th1 response, tumor immune evasion, interferon-gamma, prognostic factors, immunotherapy targets
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Adult, Aged, Cells, Cultured, Female, Hepatitis B, Hepatitis B virus, Carcinoma, Hepatocellular, Humans, Kupffer Cells, Liver Neoplasms, Male, Membrane Proteins, Middle Aged, Predictive Value of Tests, Prognosis, Sampling Studies, Signal Transduction, CD4-Positive T-Lymphocytes, Gene Expression Regulation, Neoplastic, Proportional Hazards Models, Survival Analysis, Statistics, Nonparametric, Galectins, Kaplan-Meier Estimate, Real-Time Polymerase Chain Reaction
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