Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells
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Abstract
Galectin-3 is a 31-kDa lectin that modulates T-cell responses through several mechanisms, including apoptosis, T-cell receptor (TCR) cross-linking, and TCR downregulation. We found that patients with pancreatic ductal adenocarcinoma (PDA) who responded to a granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDA vaccine developed neutralizing antibodies to galectin-3 after immunization. We show that galectin-3 binds activated antigen-committed CD8(+) T cells only in the tumor microenvironment. Galectin-3-deficient mice exhibit improved CD8(+) T-cell effector function and increased expression of several inflammatory genes. Galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3-mediated suppression of CD8(+) T cells in vitro. Lastly, galectin-3-deficient mice have elevated levels of circulating plasmacytoid dendritic cells, which are superior to conventional dendritic cells in activating CD8(+) T cells. Thus, inhibiting galectin-3 in conjunction with CD8(+) T-cell-directed immunotherapies should enhance the tumor-specific immune response.
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LAG3 ligands include MHC II, galectin-3, α-synuclein fibrils, L-SECtin, and FGL-1.
“The ligands of LAG3 are not only limited to MHC II as well as other ligands like galectin 3 (Gal‐3), α‐synuclein fibrils (α‐syn), lymph node sinusoidal endothelial cell C‐type lectin (L‐SECtin) and fibrinogen‐like protein 1 (FGL‐1) [318, 319, 320].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [320]
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- Authors
- Kouo, T., Huang, L., Pucsek, A. B., Cao, M., Solt, S., Armstrong, T., & Jaffee, E.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Cancer Immunology Research
- Published
- 2015-04-01
- Volume
- 3
- Issue
- 4
- Pages
- 412-423
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC4390508
- OpenAlex
- W2117552772
- Cited by
- 531
- References
- 36
- Citations by year
- 2026: 43 · 2025: 53 · 2024: 73 · 2023: 67 · 2022: 76 · 2021: 55 · 2020: 53 · 2019: 35 · 2018: 29 · 2017: 25 · 2016: 13 · 2015: 8
- FWCI
- 12.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P50CA062924, P30CA006973, R01CA184926)
- National Institute of General Medical Sciences (T32GM007309)
- National Institute of Allergy and Infectious Diseases (T32AI007247)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Galectins and Cancer Biology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- galectin-3, LAG-3, CD8+ T cells, plasmacytoid dendritic cells, pancreatic ductal adenocarcinoma, tumor microenvironment, T cell suppression, allogeneic vaccine, neutralizing antibodies, dendritic cell activation, antitumor immunity
- MeSH terms
- Lymphocyte Activation Gene 3 Protein, Animals, Cell Differentiation, Dendritic Cells, Female, Humans, Immune Tolerance, Interferon-gamma, Lymphocyte Activation, Pancreatic Neoplasms, Antigens, CD, Immunophenotyping, Lymphocytes, Tumor-Infiltrating, Mice, Knockout, CD8-Positive T-Lymphocytes, Cancer Vaccines, Carcinoma, Pancreatic Ductal, Galectin 3
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