Emerging glyco-based strategies to steer immune responses

Abstract

Glycan structures are common posttranslational modifications of proteins, which serve multiple important structural roles (for instance in protein folding), but also are crucial participants in cell-cell communications and in the regulation of immune responses. Through the interaction with glycan-binding receptors, glycans are able to affect the activation status of antigen-presenting cells, leading either to induction of pro-inflammatory responses or to suppression of immunity and instigation of immune tolerance. This unique feature of glycans has attracted the interest and spurred collaborations of glyco-chemists and glyco-immunologists to develop glycan-based tools as potential therapeutic approaches in the fight against diseases such as cancer and autoimmune conditions. In this review, we highlight emerging advances in this field, and in particular, we discuss on how glycan-modified conjugates or glycoengineered cells can be employed as targeting devices to direct tumor antigens to lectin receptors on antigen-presenting cells, like dendritic cells. In addition, we address how glycan-based nanoparticles can act as delivery platforms to enhance immune responses. Finally, we discuss some of the latest developments in glycan-based therapies, including chimeric antigen receptor (CAR)-T cells to achieve targeting of tumor-associated glycan-specific epitopes, as well as the use of glycan moieties to suppress ongoing immune responses, especially in the context of autoimmunity.

Keywords: autoimmunity; cancer; glycosylation; immune system; vaccination.

Fig. 1

Innate immunity and glycans play a key role in immune responses and homeostasis. Antigen‐presenting cells (APCs), such as dendritic cells and macrophages, recognize pathogens using PAMPs and DAMPs via a group of so‐called pattern recognition receptors, the most important families of these receptors being TLRs, nucleotide‐binding oligomerization domain NLRs, RIG‐I‐like receptors (RLRs), and C‐type lectin receptors (CLRs). Glycans are often key part of these interactions as well as of the following interplay between innate and adaptive immunity, thus fine‐tuning immune responses, for example, by differential stimulation of T helper (Th) cell activation and differentiation to individual cellular subsets, including regulatory T cells (Tregs) with varying functions.

Fig. 2

Overview of carrier systems used for multivalent glycan display. Multivalent high‐mannose glycan presentation on glycoclusters, polymers, antigens (proteins and peptides), liposomes, dendrimers, and nanoparticles has been successfully used for targeting C‐type lectin receptors, like DC‐SIGN, Mincle, and mannose receptor. In contrast, the C‐type lectin Mincle associates with the signaling adaptor FcRγ, which upon binding of its ligand microbial cord factor trehalose‐6,6‐dimycolate directly triggers pro‐inflammatory responses. Therefore, the adjuvanticity of Mincle ligands is widely studied within the field of vaccinology. Adapted from [67].

Fig. 3

CAR‐T represent another strategy to target distinct glycan epitopes, unique for tumor cells.

Fig. 4

Glyco‐based strategies to modulate immune responses. The fragile balance between immune homeostasis and autoimmune diseases can be guided by glycan epitope‐containing reagents. In case of collagen type II‐induced arthritis, T cells can be educated to tolerate the tissue by using glycopeptide‐loaded soluble MHC II complexes displaying the troublemaking glycan epitope, whereas in the case of anti‐MAG neuropathy, anti‐MAG IgM antibodies are scavenged by HNK‐1 glycopolymer conjugates.

Fig. 5

Sialylated tumor‐associated glycans can dampen antitumor immune response through interaction with Siglecs, a family of inhibitory receptors found on DCs. Through the interaction with, for instance, Siglec‐7. DCs instruct the differentiation of Treg, while T helper 1 (Th1) responses are inhibited, together promoting tumor growth (left). On the other hand, Siglec‐mediated inhibition might be harnessed to prevent overactive immune response in allergy, chronic inflammation, and autoimmune disease settings, for example, by using artificially designed sialylated polymers or conjugates to control unwanted T helper responses and to promote Treg differentiation (right).