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Tumor-Associated Carbohydrates and Immunomodulatory Lectins As Open access Review J Immunother Cancer: first published as 10.1136/jitc-2020-001222 on 5 October 2020. Downloaded from Tumor- associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy Natalia Rodrigues Mantuano, Marina Natoli , Alfred Zippelius , Heinz Läubli To cite: Rodrigues Mantuano N, ABSTRACT numerous biological functions.8–10 Cell Natoli M, Zippelius A, et al. During oncogenesis, tumor cells present specific surfaces and extracellular proteins are signifi- Tumor- associated carbohydrates carbohydrate chains that are new targets for cancer cantly glycosylated. In addition, glycosami- and immunomodulatory immunotherapy. Whereas these tumor-associa ted lectins as targets for cancer noglycans can be found in the extracellular carbohydrates (TACA) can be targeted with antibodies immunotherapy. Journal for matrix. Glycans are used as storage for energy ImmunoTherapy of Cancer and vaccination approaches, TACA including sialic acid- containing glycans are able to inhibit anticancer immune (glycogen), are structurally important (see 2020;8:e001222. doi:10.1136/ later for the stability of programmed cell jitc-2020-001222 responses by engagement of immune receptors on leukocytes. A family of immune-modula ting receptors death protein 1 (PD-1)) and can mediate NRM and MN contributed are sialic acid-binding Siglec receptors that have been signals. Whereas proteins undergo substan- equally. recently described to inhibit antitumor activity mediated tial post- translational modifications, in partic- by myeloid cells, natural killer cells and T cells. Other ular N- glycosylation and O- glycosylation,8–10 Accepted 28 August 2020 TACA-binding receptors including selectins have been intracellular modification of tyrosine with linked to cancer progression. Recent studies have shown 11 O- GlcNAc serves for intracellular signaling. that glycan-lectin interactions can be targeted to improve Changes of glycosylation have a significant cancer immunotherapy. For example, interactions between impact on cancer biology and cancer progres- the immune checkpoint T cell immunoglobulin and mucin- 12–15 domain containing-3 and the lectin galectin-9 are targeted sion. Of note, altered glycan structures in clinical trials. In addition, an antibody against the lectin represent antigenic targets for cancer immu- Siglec-15 is being tested in an early clinical trial. In this notherapy. In this review, we summarize how review, we summarize the previous and current efforts cancer- associated changes in glycosylation can to target TACA and to inhibit inhibitory immune receptors be used to improve cancer immunotherapy. binding to TACA including the Siglec-sialoglycan axis. http://jitc.bmj.com/ INTRODUCTION CANCER-SPECIFIC CHANGES IN GLYCOSYLATION Recent advancements in the stimulation of the Altered glycosylation is a common feature immune microenvironment and anticancer immune responses with immune checkpoint of tumor cells and leads to the formation on September 24, 2021 by guest. Protected copyright. inhibitors (ICI) has improved the outcome of of tumor- associated carbohydrates (TACA) treatments for patients and has led to impres- (figure 1). Three common changes are sive long- term remissions in some patients often associated with cancer: a) increased with advanced disease.1–5 However, primary expression of truncated or incomplete and acquired resistance significantly diminish glycans, b) increased branching of N-glycans the success of ICI and only a minority of and c) augmented or changed presence of 15 patients benefit from currently available sialic acid-containing glycans. Tumor- cell- © Author(s) (or their cancer immunotherapies.6 7 Thus, new strat- surface glycans are known to promote cancer employer(s)) 2020. Re- use egies are urgently needed in order to induce progression by affecting tumor growth, cell permitted under CC BY-NC. No long- term remissions with cancer immuno- invasiveness and negatively regulate immune commercial re- use. See rights 15–17 and permissions. Published by therapy in many more of our patients. responses. Changes of glycosylation BMJ. Carbohydrates belong to the major biomol- observed in cancer depend on the expression Department of Biomedicine, ecules of living organisms. Carbohydrates can and changes of enzymes involved in glycan Universitätsspital Basel, Basel, be attached to proteins (glycoproteins), lipids biosynthesis and glycan-modifying enzymes Switzerland and exist as chains of carbohydrates (glycos- including transferases and glycosidases aminoglycans). Glycans—carbohydrate- as well as transporter for saccharides and Correspondence to 12 14 18 Professor Heinz Läubli; containing macromolecules—are ubiquitous precursors. Expression of these glycan- heinz. laeubli@ unibas. ch in biological systems and are essential for modifying proteins are altered in cancer due Rodrigues Mantuano N, et al. J Immunother Cancer 2020;8:e001222. doi:10.1136/jitc-2020-001222 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001222 on 5 October 2020. Downloaded from lumen of internal organs. For example, mucins, highly O- glycosylated proteins such as CA19-9,30 can serve as a biomarker for some cancer types. One of the most common cancer- associated changes in glycosylation is the truncation of O- linked carbohydrate chains (figure 1).31 Usually, a GalNAc sugar residue is attached to a serine or threonine of the glycoprotein (GalNAcα1- O- Ser/ Thr, Tn antigen) and usually elongated by the T-syn - thase (core 1 β3- galactosyltransferase) in the Golgi appa- ratus that attaches a galactose residue to Tn antigen. The resulting glycan is called T antigen (sometimes also called the Thomsen- Friedenreich (TF) antigen). The T- synthase requires a chaperone for the correct folding and enzymatic activity.31 The chaperone was termed Core 1 β3- galactosyltransferase Specific Molecular Figure 1 Overview on cancer- associated glycosylation. Chaperone (COSMC).32 The X linked COSMC gene is Three main changes can be found in cancer that are mutated in various cancer types leading to the presence regulated by genetic or epigenetic alterations in genes of Tn antigen or its sialylated form, the sialyl- Tn (STn) of glycan- modifying enzymes or enzymes involved in antigen.31 Interestingly, truncated O- glycosylation is carbohydrate biosynthesis. N- glycans show often an increased branching due to increased MGAT5 expression. shown to have an immunomodulatory effect. Tn antigen Another often observed change is the truncation of O-glycans binds to macrophage galactose-type lectin on dendritic and the exposure of new tumor- associated carbohydrates cells and macrophages that inhibits the migration of (TACA) including the T antigen, Tn antigen and the sialyl- immature antigen- presenting cells (APCs) and increases Tn antigen (STn). In addition, changes of sialylation of M2- like tumor associated macrophages.33–35 both glycoproteins and glycolipids can be observed. Truncated O- glycans represent epitopes which may Increased sialylation (hypersialylation) is often observed. The selectively target cancer cells. Various cancer tissues introduction of the non- human sialic acid Neu5Gc can also have been analyzed for the expression for the T, Tn and be observed. Fuc, fucose; GlcNAc, N- acetyl- glucosamine; STn antigen.36–38 The human- mucin 1 (MUC1) is over- Gal, galactose; GalNAc, N- acetyl- galactosamine; Glc, glucose; Man, mannose; N- acetyl- neuraminic acid; Neu5Gc, expressed in many adenocarcinomas, presenting high N- glycosyl- neuraminic acid. levels of truncated glycans as STn-MUC1, Tn- MUC1 and T- MUC-1. Yet, these antigens are rarely expressed in normal tissue compared with cancer tissue.39–44 Further to genetic and epigenetic alterations and differ between studies are needed to determine the specificity of the cancer types. expression patterns if we consider to target these epitopes http://jitc.bmj.com/ Changes in sialylation with antibodies and chimeric antigen receptors (CARs). Cancer- associated glycans often exhibit an increased amount of sialic acid. Augmented sialylation of tumor Altered branching of N-glycoproteins cells has been correlated with a metastatic phenotype Increased branching of N-glycans, mediated by β1,6- N- 12 15 and poor prognosis in patients with cancer.19 20 Sialic acetylglucosaminyltransferase V (MGAT5, figure 1), can influence cell adhesion, migration and metastasis acids are predominantly found at the non-reducing end on September 24, 2021 by guest. Protected copyright. 45 46 of N- linked and O- linked glycans attached to proteins of tumor cells. Upregulation of MGAT5 has also or glycolipids.21 Hypersialylation facilitates interactions been shown to directly influence cytokine signaling and 47 with sialic acid binding receptors such as selectins and tumor progression while the knockdown of Mgat5 led + Siglecs with consequences for cancer progression. More- to activation of CD4 T cells and macrophages in breast 48 over, the incorporation of the non- human sialic acid cancer. Altered N-glycosylation of immune cells could N- glycolyl- neuraminic acid (Neu5Gc) into glycans and also affect the antitumor immune response. Increased the interaction with circulating anti-Neu5Gc antibodies branching of N- glycans can directly inhibit T cell activa- 49 50 influences cancer progression.22–26 Neu5Gc is biosynthe- tion by increasing T cell receptor (TCR) clustering. 49 sized from N- acetyl- neuraminic acid (Neu5Ac) via the This effect was attributed to interaction with galectin-3. enzyme
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