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Cancer-Associated Glycosphingolipids As Tumor Markers and Targets for Cancer Immunotherapy

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Cancer-Associated Glycosphingolipids As Tumor Markers and Targets for Cancer Immunotherapy International Journal of Molecular Sciences Review Cancer-Associated Glycosphingolipids as Tumor Markers and Targets for Cancer Immunotherapy Sophie Groux-Degroote * and Philippe Delannoy CNRS, UMR 8576—UGSF—Unité de Glycobiologie Structurale et Fonctionnelle, University of Lille, F-59000 Lille, France; [email protected] * Correspondence: [email protected] Abstract: Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties. Disialylated gangliosides GD2 and GD3 are considered as markers of neuroectoderm origin in tumors, whereas fucosyl-GM1 is expressed in very few normal tissues but overexpressed in a variety of cancers, especially in small cell lung carcinoma. These gangliosides are absent in most normal adult tissues, making them targets of interest in immuno-oncology. Passive and active immunotherapy strategies have been developed, and have shown promising results in clinical trials. In this review, we summarized the current knowledge on GD2, GD3, and fucosyl-GM1 expression in health and cancer, their biosynthesis pathways in the Golgi apparatus, and their biological roles. We described how their overexpression can affect intracellular signaling pathways, increasing the malignant phenotypes of cancer cells, including their metastatic potential and invasiveness. Finally, the different strategies used to target these tumor-associated gangliosides for immunotherapy were discussed, including the use and development of monoclonal antibodies, Citation: Groux-Degroote, S.; vaccines, immune system modulators, and immune effector-cell therapy, with a special focus on Delannoy, P. Cancer-Associated adoptive cellular therapy with T cells engineered to express chimeric antigen receptors. Glycosphingolipids as Tumor Markers and Targets for Cancer Keywords: ganglioside; cancer; glycosyltransferase; immunotherapy; transcriptional regulation; Immunotherapy. Int. J. Mol. Sci. 2021, Golgi apparatus 22, 6145. https://doi.org/10.3390/ ijms22116145 Academic Editors: Nicola Silvestris, 1. Biosynthesis and Expression of Cancer-Associated Gangliosides Afshin Derakhshani and Oronzo Brunetti Gangliosides are cell surface glycosphingolipids that play important functional roles in cell-cell recognition, cell adhesion, and signal transduction. Their carbohydrate moiety is Received: 29 April 2021 synthesized in the Golgi apparatus by the sequential action of different glycosyltransferases. Accepted: 3 June 2021 Modifications in expression patterns of gangliosides during development or diseases can Published: 7 June 2021 be largely attributed to changes of the expression of glycosyltransferases involved in their synthesis and that are spatiotemporally regulated both at the transcriptional and post- Publisher’s Note: MDPI stays neutral translational levels [1]. Regulation at the transcriptional level includes transcription factors with regard to jurisdictional claims in (TF), but also epigenetic modifications and can explain most of the glycolipid composition published maps and institutional affil- changes observed during development and cancer [2,3]. iations. Although gangliosides are mostly expressed in neural tissue, abundant expression of specific gangliosides has been observed in some tumors. A characteristic feature of small cell lung carcinoma (SCLC) is the aberrant and abundant expression of ganglioside 2 3 Fuc-GM1 (fucosylated monosialotetrahexosylganglioside or IV FucII Neu5AcGg4Cer), Copyright: © 2021 by the authors. whereas the ectopic expression of b-series gangliosides and their O-acetylated derivatives Licensee MDPI, Basel, Switzerland. is associated with cancers of neuro-ectoderm origin. This article is an open access article distributed under the terms and 1.1. Biosynthesis Pathways of Cancer-Associated Gangliosides conditions of the Creative Commons The biosynthesis of tumor-associated gangliosides starts from lactosylceramide (Lac- Attribution (CC BY) license (https:// Cer, Gg2Cer) by the transfer in the Golgi apparatus of a first sialic acid residue catalyzed creativecommons.org/licenses/by/ 3 by the GM3 synthase ST3Gal V to form GM3 (II Neu5AcGg2Cer) (Figure1). The GM3 4.0/). Int. J. Mol. Sci. 2021, 22, 6145. https://doi.org/10.3390/ijms22116145 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 15 1.1. Biosynthesis Pathways of Cancer‐Associated Gangliosides Int. J. Mol. Sci. 2021, 22, 6145The biosynthesis of tumor‐associated gangliosides starts from lactosylceramide (Lac‐ 2 of 15 Cer, Gg2Cer) by the transfer in the Golgi apparatus of a first sialic acid residue catalyzed by the GM3 synthase ST3Gal V to form GM3 (II3Neu5AcGg2Cer) (Figure 1). The GM3 syn‐ thase, encoded synthase,by the ST3GAL5 encoded gene, by the isST3GAL5 the only sialyltransferasegene, is the only sialyltransferasethat uses LacCer that as an uses LacCer as an acceptor substrateacceptor [4]. However, substrate [it4]. was However, demonstrated it was demonstrated that the product that the of productthe ST3GAL5 of the ST3GAL5 gene gene was also ablewas to also synthesize able to synthesize GM4 from GM4 galactosylceramide, from galactosylceramide, specifically specifically expressed in expressed in the the brain and kidneysbrain and [5]. kidneys Three GM3 [5]. Three synthase GM3 isoforms synthase with isoforms different with differentN‐terminal N-terminal cyto‐ cytoplasmic plasmic tail lengthstail lengths were characterized were characterized [6]. [6]. LacCer synthase GM3 synthase GD3 synthase (β4Gal T6) (ST3Gal V) (ST8Sia I) CasD1 Ac 8 8 3 3 3 Cer 1 Cer 1 4 Cer 1 4 Cer 1 4 Cer 1 4 Glc Ce r LacCer GM3 GD3 Ac 9GD3 3 3 3 II Neu5AcGg2Cer II (Neu5Ac)2Gg2Cer II (Ac9Neu5Ac)2Gg2Cer GM2/GD2 synthase (β4GalNAcT1) CasD1 Ac 8 8 3 3 3 Cer Cer 1 4 4 1 4 4 Cer 1 4 4 GM2 GD2 Ac9GD2 3 3 3 II Neu5AcGg3Cer II (Neu5Ac)2Gg3Cer II (Ac9Neu5Ac)2Gg3Cer GM1/GD1b synthase (β3GalT4) 3 Cer 1 4 4 3 GM1 3 II Neu5AcGg4Cer FUT1 /2 3 2 Cer 1 4 4 3 Fuc os yl-GM1 2 3 IV FucII Neu5AcGg 4Cer Glc Gal GalNAc Neu5Ac Fuc Figure 1. ProposedFigure 1. biosynthesis Proposed biosynthesis pathway for pathway tumor-associated for tumor gangliosides.‐associated gangliosides. Tumor-associated Tumor gangliosides‐associated gan are‐ synthesized from lactosyl-ceramidegliosides are synthesized (LacCer) by from the action lactosyl of‐ceramide the GM3 (LacCer) synthase by ST3Gal the action V that of transfersthe GM3 synthase a first sialic ST3Gal acid residue to form GM3V (precursor that transfers of the a first a-series sialic gangliosides). acid residue to The form elongation GM3 (precursor of GM3 isof performed the a‐series by gangliosides). the sequential The action of the β4GalNAcelongation T1 and β3Gal of GM3 T4 to is form performed GM1, whichby the issequential further fucosylated action of the by β4GalNAc the α1,2-fucosyltransferases T1 and β3Gal T4 to FUT1form and FUT2. GM1, which is further fucosylated by the α1,2‐fucosyltransferases FUT1 and FUT2. Alternatively, Alternatively, the action of the GD3 synthase ST8Sia I converts GM3 in GD3, the precursor of the b-series gangliosides, the action of the GD3 synthase ST8Sia I converts GM3 in GD3, the precursor of the b‐series gangli‐ which is the substrate of the β4GalNAc T1 that forms GD2. Finally, GD3 and GD2 can be acetylated by CASD1 sialate osides, which is the substrate of the β4GalNAc T1 that forms GD2. Finally, GD3 and GD2 can be O-acetyl-transferaseacetylated on by theCASD1 C9 position sialate O of‐acetyl sialic‐ acidstransferase to form on 9- theO-acetylated C9 position GD3 of sialic (9-O acidsAcGD3) to form and 9 9-‐OO‐-acetylatedacet‐ GD2 (9-OAcGD2),ylated respectively. GD3 (9‐O ItAcGD3) has also beenand 9 proposed‐O‐acetylated that O-acetylated GD2 (9‐OAcGD2), GD3 can respectively. be formed by It thehas transfer also been of CMP-Neu5,9Ac pro‐ 2 on GM3 byposed the GD3 that synthase.O‐acetylated The GD3 effects can of beβ formed4GalNAc by T1the andtransferβ3Gal of CMP T4 on‐Neu5,9Ac OAcGD32 andon GM3 OAcGD2, by the respectively, GD3 are currently unknown.synthase. The effects of β4GalNAc T1 and β3Gal T4 on OAcGD3 and OAcGD2, respectively, are currently unknown. Little is known about ST3GAL5 gene regulation. However, it was shown that Zeb1, Little is knowna transcription about ST3GAL5 factor gene associated regulation. to epithelial-mesenchymal However, it was shown transition that Zeb1, (EMT), a induces the transcription factorexpression associated of the to GM3 epithelial synthase‐mesenchymal via the binding transition of Zeb1 (EMT), to the inducesSt3gal5 thepromoter and the expression of thesuppression GM3 synthase of microRNA-mediated via the binding of Zeb1 repression to the of St3gal5St3gal5 promoter[7]. and the suppression of microRNAThereafter,‐mediated GM3 repression can be elongated of St3gal5 by [7]. the sequential action of the GM2/GD2 syn- thase β4GalNAcT1 and the GM1/GD1b synthase β3GalT4 to form GM1 (Neu5AcGg4Cer), which belongs to the a-series gangliosides (Figure1)[ 8,9]. The β4GalNAcT1 is active on all series of gangliosides and converts LacCer, GM3, GD3, and GT3 (the precursors of the 0, a, b and c-series gangliosides, respectively) into GA2, GM2, GD2, and GT2, respectively Int. J. Mol. Sci. 2021, 22, 6145 3 of 15 (Figure1)[ 10,11]. Similarly, the β3GalT4 equally uses GM2 and GD2 as acceptor sub- strates [10]. Both enzymes can form functional complexes in the trans-Golgi network, which may optimize complex glycolipid biosynthesis by a channeling effect [12]. GM1 can be further
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