Engineering galectin-glycan interactions for immunotherapy and immunomodulation

Abstract

Galectins, a 15-member family of soluble carbohydrate-binding proteins, are receiving increasing interest as therapeutic targets for immunotherapy and immunomodulation due to their role as extracellular signals that regulate innate and adaptive immune cell phenotype and function. However, different galectins can have redundant, synergistic, or antagonistic signaling activity in normal immunological responses, such as resolution of inflammation and induction of antigen-specific tolerance. In addition, certain galectins can be hijacked to promote progression of immunopathologies, such as tumor immune privilege, metastasis, and viral infection, while others can inhibit these processes. Thus, eliciting a desired immunological outcome will likely necessitate therapeutics that can precisely enhance or inhibit particular galectin-glycan interactions. Multivalency is an important determinant of the affinity and specificity of natural galectin-glycan interactions, and is emerging as a key design element for therapeutics that can effectively manipulate galectin bioactivity. This minireview surveys current molecular and biomaterial engineering approaches to create therapeutics that can stabilize galectin multivalency or recapitulate natural glycan multivalency (i.e. "the glycocluster effect"). In particular, we highlight examples of using natural and engineered multivalent galectins for immunosuppression and immune tolerance, with a particular emphasis on treating autoimmune diseases or avoiding transplant rejection. In addition, we present examples of multivalent inhibitors of galectin-glycan interactions to maintain or restore T-cell function, with a particular emphasis on promoting antitumor immunity. Finally, we discuss emerging opportunities to further engineer galectin-glycan interactions for immunotherapy and immunomodulation.

Keywords: Biomaterial; bionanoscience; engineering; glycan; immunobiology; immunology.

Figure 1

Classification of galectins by structure and an overview of their modulation of immune cell function. (A color version of this figure is available in the online journal.)

Figure 2

Schematic overview of therapeutic approaches to harness galectin–glycan interactions to suppress T-cell function (left) or inhibit galectin–glycan interactions to restore T-cell function (right). (A color version of this figure is available in the online journal.)

Figure 3

A stable dimeric variant of galectin-1 based on an Fc fusion protein. (a) The dimeric and monomeric states of the Gal-1hFc fusion protein. (b) Binding of Gal1-hFc to HL-60 cells. (c) Gal-1hFc induced apoptosis of Th1 and Th17, but not Th2 effector T cell subsets in a carbohydrate-dependent manner, similar to wild-type galectin-1. (d-e) In a murine skin hypersensitivity model, Gal-1hFc delivery (d) significantly decreased mononuclear and granulocytic infiltrates and (e) suppressed changes in ear thickness resulting from inflammation. Adapted from Cedeno-Laurent et al. (A color version of this figure is available in the online journal.)

Figure 4

Self-assembled glycopeptide nanofibers as inhibitors of galectin-1. (a) Galectin-1 binding nanofibers fabricated via self-assembly of the glycopeptide, GlcNAc-Q11, and its non-glycosylated analog, followed by conversion of nanofibrillar GlcNAc to LacNAc via a glycosyltransferase enzyme. (b,c) Data demonstrating that LacNAc-Q11 nanofibers have higher affinity for galectin-1 than galectin-3, and that LacNAc-Q11 nanofibers have higher affinity for galectins than GlcNAc-Q11 nanofibers. (d) LacNAc-Q11 nanofibers inhibited Jurkat T cell agglutination via galectin-1, an early marker of apoptosis. (e) LacNAc-Q11 nanofibers inhibited apoptosis of Jurkat T cells via galectin-1, but failed to inhibit galectin-3, likely due to observed differences in nanofiber-galectin binding affinity (b,c). Adapted from Restuccia et al. (A color version of this figure is available in the online journal.)