Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia
Open accessAbstract
Tumor-associated immune suppression can lead to defective T cell-mediated antitumor immunity. Here, we identified a unique phenotype of exhausted T cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the coexpression of Tim-3 and PD-1 on CD8+ T cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 coexpression increased during AML progression. PD-1+Tim-3+ CD8+ T cells were deficient in their ability to produce IFN-γ, TNF-α, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3+PD-1- KO CD8+ T cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced T-regulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8+ T cells. Whereas blocking the PD-1/PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing—albeit not eliminating—both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8+ T-cell exhaustion in patients with hematologic malignancies such as advanced AML.
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Tim-3, LAG-3, and BTLA are co-expressed with PD-1, and this co-expression strongly correlates with immune dysfunction in cancer patients.
“In the course of defining exhausted PD-1+ T cells, T cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) [39,41], lymphocyte-activation gene (LAG)-3 [38], and the B and T-cell lymphocyte attenuator (BTLA, CD272) [42,43] were found to be co-expressed with PD-1, and the co-expression has been strongly correlated with immune dysfunction in patients with cancer.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [41]
T cells co-expressing these surface molecules show significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.
“In these studies, T cells co-expressing these surface molecules show a significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [41]
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Self-citation
- Authors
- Zhou, Q., Munger, M. E., Veenstra, R. G., Weigel, B. J., Hirashima, M., Munn, D. H., Murphy, W. J., Azuma, M., Anderson, A. C., Kuchroo, V. K., & Blazar, B. R.
- Affiliations
- Augusta University (US)
- Kagawa University (JP)
- Tokyo Medical and Dental University (JP)
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2011-04-28
- Volume
- 117
- Issue
- 17
- Pages
- 4501-4510
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3099570
- OpenAlex
- W1976105607
- Cited by
- 675
- References
- 51
- Citations by year
- 2026: 21 · 2025: 49 · 2024: 46 · 2023: 53 · 2022: 45 · 2021: 56 · 2020: 62 · 2019: 47 · 2018: 59 · 2017: 54 · 2016: 38 · 2015: 57 · 2014: 23 · 2013: 34 · 2012: 24
- FWCI
- 13.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Children's Cancer Research Fund
- National Institutes of Health (CA72669)
- U.S. Public Health Service (P01 056299)
- Japan Society for the Promotion of Science (23256004, 22590360)
- National Heart, Lung, and Blood Institute (R01HL056067)
- National Cancer Institute (R01CA 72 669, R01CA072669, R01CA112431, P01CA065493)
- National Institute of Allergy and Infectious Diseases (R01AI034495, R01AI-34495, P01AI056299)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Galectins and Cancer Biology
- Keywords
- TIM-3, PD-1, CD8+ T cell exhaustion, acute myeloid leukemia, galectin-9, PD-L1, regulatory T cells, tumor immunosuppression, cytokine production, liver metastasis, hematologic malignancies
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, Antibodies, Monoclonal, Antigens, Surface, Genes, Lethal, Liver, Mice, Inbred C57BL, Phenotype, Receptors, Virus, Signal Transduction, Leukemia, Myeloid, Acute, Gene Expression, Immunophenotyping, Mice, Knockout, CD8-Positive T-Lymphocytes, Galectins, Apoptosis Regulatory Proteins, Mice, Programmed Cell Death 1 Receptor
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