Our laboratory investigates the regulatory roles of complex N-linked glycans in cellular processes and disease in humans. N-glycosylation within the Golgi apparatus controls macromolecular complex formation on the cell surface and thereby determines cell growth, differentiation, and disease. The size and branching of the N-glycans control galectin binding and the assembly of the galectin–glycoprotein lattice, a structured network that governs the distribution, clustering, and endocytosis of cell-surface glycoproteins in a highly ordered fashion.
Immune Regulation and Autoimmunity
N-glycan branching deficiencies have a profound influence on immune function. In T cells, reduced branching reduces receptor clustering and signaling thresholds, diminishes CTLA-4 surface maintenance, and biases differentiation towards pro-inflammatory TH1 and TH17 subsets but limits Treg and TH2 subsets. These changes cause hyperactivation and autoimmune pathology in human systems. N-glycan branching deficiency also impairs B cell development and tolerance, promotes antigen-presenting cell–mediated demyelination by hyper-signaling through Toll-like receptors, and inhibits repair myelin by oligodendrocyte precursor cells. All of these deficiencies combine with genetic and environmental risk factors to produce multiple sclerosis (MS).
Cancer Biology and Immunotherapy
Malignant transformation is almost invariably coupled with aberrant N- and/or O-linked glycosylation, which promotes tumor growth, invasion, and metastasis. Tumor-associated carbohydrate antigens (TACAs) are thus appealing therapeutic targets, yet conventional antibodies bind poorly to glycans. To bypass this issue, we have developed Glycan-dependent T cell Recruiter (GlyTR) immunotherapeutics with support from the NCI Cancer Moonshot program. These bi-specific lectin-based structures have high-avidity, density-dependent binding to branched N-glycans (GlyTR1) or an unselective panel of TACAs, like Tn, sialyl-Tn, LacDiNAc, and GD2 (GlyTR2). GlyTRs activate T cells with femtomolar potency, enabling effective pan-cancer killing at ultralow effector-to-target ratios, yet demonstrating a lack of off-target toxicity in models optimized for human-like expression of glycan.
Our mission is to advance fundamental understanding of glycan regulation and translate these insights into transformative therapies for autoimmune disease and cancer.