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Studies on a Sulfoxide-Bridged Tn Antigen Mimetic: Interaction with Macrophage Galactose Lectin and Inhibition of
Andrea Sodini1, Emanuele Casali2, Maria Alejandra Travecedo3,4
1Department of Chemistry, DICUS, University of Florence, via della Lastruccia 3-13, Sesto Fiorentino 50019, Italy.
Abstract:
Aberrant O-glycosylation is a defining hallmark of epithelial cancers, where truncated mucin-type glycans such as Tn and sialyl-Tn (sTn) are prominently displayed. Despite their tumor specificity, these tumor-associated carbohydrate antigens (TACAs) elicit only weak immune responses, limiting their impact in vaccine-based immunotherapy. Growing evidence implicates two major factors in this poor immunogenicity: the intrinsic engagement of Tn/sTn with the immunosuppressive macrophage galactose-type lectin (MGL) on antigen-presenting cells and the "self" nature of Tn/sTn mucin carriers such as MUC1. Both processes critically depend on the N-acetyl functionalities of the Tn determinant. We previously developed a stable Tn mimetic, 2-deoxy-2-thio-α-O-galactoside (compound 1), which lacks the NHAc group and exhibits notable immunostimulatory properties in vivo. In this study, we provide new structural insights into the role of the NHAc moiety in the mimetic 1 presentation and its interaction with MGL, thereby advancing the design principles for next-generation Tn analogues with improved immunological behavior. An additional focus is on the pathogenic upregulation of sTn in tumors, primarily driven by overexpression of the sialyltransferase ST6GALNAC1. We demonstrate that mimetic 1 and its oxidized analogue 2 act as inhibitors of ST6GALNAC1representing, to the best of our knowledge, the first reported monosaccharide inhibitors of this enzyme. Although the inhibitory potency is modest, these compounds establish a valuable chemical starting point for targeting cancer-associated sialylation, an effort currently constrained by the lack of structural information for ST6GALNAC1.
Insights
This study explores cancer-associated glycans like Tn and sialyl-Tn (sTn), revealing how a modified Tn mimetic (compound 1) enhances anti-tumor immunity by interacting with MGL and inhibiting ST6GALNAC1. This advances cancer immunotherapy design.
Area of Science:
- Glycobiology and Cancer Immunology
- Chemical Biology and Drug Discovery
Background:
- Aberrant O-glycosylation, specifically Tn and sialyl-Tn (sTn) glycans, is a hallmark of epithelial cancers.
- These tumor-associated carbohydrate antigens (TACAs) exhibit poor immunogenicity due to MGL engagement and self-nature, hindering vaccine-based immunotherapy.
- The N-acetyl group is critical for Tn/sTn interaction with MGL and for their immunosuppressive properties.
Purpose of the Study:
- To elucidate the structural role of the N-acetyl group in Tn mimetic (compound 1) presentation and MGL interaction.
- To advance the design of next-generation Tn analogues with improved immunological behavior.
- To investigate the inhibitory potential of compound 1 and its analogue 2 against ST6GALNAC1, a key enzyme in sTn upregulation.
Main Methods:
- Structural analysis of Tn mimetic (compound 1) presentation and its interaction with macrophage galactose-type lectin (MGL).
- In vivo assessment of immunostimulatory properties of compound 1.
- Enzyme inhibition assays using compound 1 and analogue 2 against sialyltransferase ST6GALNAC1.
Main Results:
- Compound 1, lacking the N-acetyl group, demonstrates immunostimulatory properties in vivo.
- New structural insights reveal the role of the N-acetyl moiety in compound 1 presentation and MGL interaction.
- Compound 1 and analogue 2 inhibit ST6GALNAC1, representing the first reported monosaccharide inhibitors of this enzyme.
Conclusions:
- The N-acetyl group is crucial for the immunosuppressive functions of Tn/sTn glycans.
- Compound 1 offers a promising starting point for developing novel Tn analogues with enhanced anti-tumor immune responses.
- Compound 1 and analogue 2 provide a chemical foundation for targeting cancer-associated sialylation via ST6GALNAC1 inhibition.
