Glycosylation in the tumor immune response: the bitter side of sweetness

Abstract

Glycosylation is the most structurally diverse form of post-translational modification (PTM) of proteins that affects a myriad of cellular processes. As a pivotal regulator of protein homeostasis, glycosylation notably impacts the function of proteins, spanning from protein localization and stability to protein-protein interactions. Aberrant glycosylation is a hallmark of cancer, and extensive studies have revealed the multifaceted roles of glycosylation in tumor growth, migration, invasion and immune escape. Over the past decade, glycosylation has emerged as an immune regulator in the tumor microenvironment (TME). Here, we summarize the intricate interplay between glycosylation and the immune system documented in recent literature, which orchestrates the regulation of the tumor immune response through endogenous lectins, immune checkpoints and the extracellular matrix (ECM) in the TME. In addition, we discuss the latest progress in glycan-based cancer immunotherapy. This review provides a basic understanding of glycosylation in the tumor immune response and a theoretical framework for tumor immunotherapy.

1. Introduction

Glycosylation is a common form of protein and lipid modification by the covalent attachment of saccharides to proteins and lipids. The major types of glycosylation in mammals include N-glycosylation, O-glycosylation, O-GlcNAcylation, GPI-anchored glycoproteins, and glycosaminoglycans [1]. N-glycosylation, in which N-glycans are attached to asparagine within the conserved N-X-S/T sequon (where X represents any amino acid excluding proline) in peptides, frequently occurs in membrane proteins [1]. All N-glycans possess a core pentasaccharide; however, the diversity of monosaccharides and the complexity of linking patterns result in different types of N-glycans, which are divided into high-mannose, hybrid, and complex types [2]. In addition to N-glycosylation, O-glycosylation and O-GlcNAcylation occur at serine/threonine (S/T) residues [1]. O-glycosylation often refers to the glycosylation of glycans initiated by N-acetylgalactosamine (GalNAc). Biosynthesis of N-glycans is initiated in the endoplasmic reticulum (ER) and further elongated in the Golgi apparatus, while the entire synthesis of O-glycans occurs in the Golgi apparatus [3]. In contrast to N-glycans and O-glycans, O-GlcNAcylation is a unique monosaccharide β-N-acetylglucosamine (GlcNAc) modification that predominantly occurs in intracellular proteins and is mediated solely by O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA) [4].

Glycosylation functions as a critical regulator of multiple physiopathological processes, including signal transduction and communication, invasion, cell–matrix interactions and immune modulation [5]. Therefore, deregulation of glycosylation is closely associated with tumor development and progression. Accumulating evidence highlights that aberrant glycosylation plays a pivotal role in tumor immunity through influencing the interaction of glycosylation receptors, lectins and ligands on the cell surfaces of tumor cells and immune cells. For example, tumor cells secrete galectins to promote regulatory T cells (Tregs) and T-cell exhaustion by impairing TME homeostasis [6–9]. The binding of sialylated glycans and sialic acid-binding immunoglobulin-like lectin (siglec) receptors remodeled the immunosuppressive TME through activating the tumor-promoting phenotype of tumor-associated macrophages (TAMs), repressing the activation of natural killer (NK) cells and dendritic cell-mediated antigen presentation and subsequent T-cell responses [10–14]. Aberrant glycosylation also regulates the interaction between immune checkpoint molecules and their corresponding ligands by affecting their stability and/or binding affinity [15]. Thus, in-depth analysis of the role of glycosylation in the tumor immune response and how aberrant glycan structures modulate tumor-mediated immune evasion may provide new and viable strategies for potential immunotherapy.