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Metabolic inhibition of galectin-1-binding carbohydrates accentuates antitumor immunity
Filiberto Cedeno-Laurent1, Matthew J Opperman, Steven R Barthel
1Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Abstract:
Galectin-1 (Gal-1) has been shown to play a major role in tumor immune escape by inducing apoptosis of effector leukocytes and correlating with tumor aggressiveness and disease progression. Thus, targeting the Gal-1/Gal-1 ligand axis represents a promising cancer therapeutic approach. Here, to test the Gal-1-mediated tumor immune evasion hypothesis and demonstrate the importance of Gal-1-binding N-acetyllactosamines in controlling the fate and function of antitumor immune cells, we treated melanoma- or lymphoma-bearing mice with peracetylated 4-fluoro-glucosamine (4-F-GlcNAc), a metabolic inhibitor of N-acetyllactosamine biosynthesis, and analyzed tumor growth and immune profiles. We found that 4-F-GlcNAc spared Gal-1-mediated apoptosis of T cells and natural killer (NK) cells by decreasing their expression of Gal-1-binding determinants. 4-F-GlcNAc enhanced tumor lymphocytic infiltration and promoted elevations in tumor-specific cytotoxic T cells and IFN-γ levels, while lowering IL-10 production. Collectively, our data suggest that metabolic lowering of Gal-1-binding N-acetyllactosamines may attenuate tumor growth by boosting antitumor immune cell levels, representing a promising approach for cancer immunotherapy.
Insights
Targeting galectin-1 (Gal-1) with 4-F-GlcNAc inhibits tumor immune evasion. This approach boosts antitumor immune cells, reducing tumor growth and offering a promising cancer immunotherapy strategy.
Area of Science:
- Immunology
- Cancer Biology
- Metabolic Therapeutics
Background:
- Galectin-1 (Gal-1) promotes tumor immune escape by inducing effector leukocyte apoptosis, correlating with tumor aggressiveness.
- Targeting the Gal-1/galectin-1 ligand axis is a potential cancer therapeutic strategy.
Purpose of the Study:
- To test the galectin-1-mediated tumor immune evasion hypothesis.
- To demonstrate the role of galectin-1-binding N-acetyllactosamines in controlling antitumor immune cells.
- To evaluate the efficacy of metabolic inhibition of N-acetyllactosamine biosynthesis in vivo.
Main Methods:
- Melanoma- or lymphoma-bearing mice were treated with peracetylated 4-fluoro-glucosamine (4-F-GlcNAc).
- 4-F-GlcNAc is a metabolic inhibitor of N-acetyllactosamine biosynthesis.
- Tumor growth and immune profiles were analyzed.
Main Results:
- 4-F-GlcNAc treatment reduced galectin-1-mediated apoptosis of T cells and NK cells by decreasing their galectin-1-binding determinants.
- Enhanced tumor lymphocytic infiltration and increased tumor-specific cytotoxic T cells were observed.
- Elevated IFN-γ levels and reduced IL-10 production were noted in treated mice.
Conclusions:
- Metabolic lowering of galectin-1-binding N-acetyllactosamines attenuates tumor growth.
- This approach enhances antitumor immune cell activity, representing a promising cancer immunotherapy strategy.
