The Blessed Union of Glycobiology and Immunology
Edit
This entry is adapted from the peer-reviewed paper 10.3390/medicines10020015
The fields of cancer glycobiology and glycobiology of infectious diseases provide crucial information concerning the cell surface glycoconjugates, as they play an important role in immunosurveillance during the development and establishment of certain pathologies. Furthermore, screening for atypical glycophenotypes culminates in the construction and modulation of an innate and adaptive immune response, mainly because glycans are biological structures that are very well conserved by evolution and are naturally heterogeneous, and end up acting as carriers of biological information that are decoded by families of proteins known as lectins. The effects of the structural recognition of glycans by these receptors, present mainly in cells of the immune system, are paramount in defining the immune responses. Therefore, those receptors are subjected to subversion of the host response against certain pathologies, being involved in the persistence of infections and tumors resistant to chemotherapy and increased metastatic potential.
glycoimmunology glycoconjugates lectins galectins

1. Cell Surface Glycoconjugates

For the last 30 years, it has been well accepted that glycans cover the cell surface of all living cells [1][2]. The first glycoprotein identified in eukaryotes was described over 80 years ago [3]. At that time, it was not thought that cell surface glycoconjugates could influence the behavior of different cell types. Further studies have confirmed that this important type of posttranslational modification (PTM), which is named glycosylation, is not restricted to higher organisms [2]. Glycan-carrying proteins have also been found in parasitic protozoa, virus, fungi and prokaryotes, such as bacteria and archaebacteria [4][5][6][7][8].
Although the expression of glycoproteins is a common feature among different organisms, glycans and/or monosaccharide structures are differentially expressed among them. A clear example are the mammalian cells, which express glycans much more diversely than other organisms [9]. Considering that the glycans carried by glycoproteins are fundamental for life, it would be plausible to propose that such differences may have played an important role in speciation, and in the formation of different organs and tissues in multicellular organisms [10]. This explanation highlights the importance of understanding glycan biology in human health and disease, mainly because there is also a diversified expression of receptors with affinity to specific glycoconjugates, such as the differentiated expression of types of galectins in different tissues of the organism [11]. Furthermore, during development, in the phases of mammalian fetal life, there is differential expression of glycoconjugates in relation to normal adult tissues [12]. In mammalian cells, during glycoprotein biosynthesis, these molecules may be transferred from the endoplasmic reticulum to the Golgi apparatus, and finally transported to the cell membrane [9], where they are capable of influencing the behavior of different cell types, including cells of the immune system [13][14].
As it is an emerging field within immunology and remains a very little commented subject in the classrooms of different biomedical courses [15], before addressing the impact of glycan structures carried by proteins in cells of the immune system, it is important to emphasize the concept of glycosylation, which is mediated by a harmonized set of enzymes, named glycosyltransferases and glycosidases [16]. While glycosyltransferases are responsible for the transfer of a sugar from a nucleotide sugar donor to a substrate, the glycosidases catalyze the hydrolysis of glycosidic bonds in glycan structures [17]. Today, it is well known that genes encoding this glycosylation machinery represent over 1% of the total genome [18][19]. These enzymes are expressed in a finely regulated way, which depends on cell activation, metabolic status and microenvironmental features [20].

2. N-Glycans in Cancer Immunotherapy

Cancer cells present an altered repertoire of glycoconjugates and this aberrant glycosylation pattern has been established as a cancer hallmark [21] (Figure 1). Regarding N-glycans, the β1,6-GlcNAc–branched N-glycans are widely overexpressed in cancer cells, being associated with increased expression of N-acetylglucosaminyltransferase V (GnT-V), responsible for its biosynthesis, which is encoded by the MGAT5 gene [22][23]. Immune evasion is another one of the cancer hallmarks, occurring through varied mechanisms, such as downregulation of MHC class I [24] and T cell death induction [25]. Several glycoconjugates have been associated with protection of tumor cells against the immune system attack [26].
Figure 1. Glycosylation changes in cancer cells compared to healthy tissues. Normal pattern of glycosylations are shown in the left panel, whereas the right is associated with cancer cells. Changes in O- and N-linked glycan structures are displayed, as well as the differences between Sialyl Lewis A and Sialyl Lewis X.
In a remarkable and well-designed work, Silva and colleagues observed that human samples from colorectal cancer presented high expression of β1,6-GlcNAc-branched N-glycans and Gnt-V enzyme. An increase in the differentiation or recruitment of Foxp3+ Tregs was also observed, which is associated with immunosuppression in the tumor microenvironment. Furthermore, the coculture of MKN45 T5, cells that overexpress MGAT5, and PBMCs demonstrated that the increase in the biosynthesis of branched N-linked glycans led to the internalization of MHC-I, reduced release of the proinflammatory cytokines IL-6 and IL-8, and increased release of inhibitory cytokine TGF-β. This was associated with masking of immunogenic glycan mannose epitopes which are recognized by antigen-presenting cells (APC), such as DCs that express glycan-recognizing receptors, namely DC-SIGN and MR. On the other hand, compromising the appearance of atypical N-glycan structures on the surface of tumor cells, either by using inhibitors or by knocking out the MGAT5 gene, led to an increase in release of proinflammatory cytokines and in the antitumor immune response. These findings show the importance of N-glycosylation in modulation antitumor immune response and, therefore, cancer immunotherapy [27].
β1,6-GlcNAc–branched N-glycans and MGAT5 also present an essential role in regulation of the immune system, since it has been widely reported that mice deficient in MGAT5, and therefore β1,6-GlcNAc–branched N-glycans, are highly susceptible to autoimmune diseases [28][29]. Furthermore, branched N-glycans also present a central role in T cell biology targeting different T cell receptors (such as TCR, CD25, and CD4), thereby regulating T cell proliferation, T cell differentiation, T cell signaling and the production of inflammatory cytokines [30].
One mechanism of immune evasion that has been explored in recent years as a target for cancer immunotherapy is the PD-1–PD-L1 pathway. Programmed cell death 1 (PD-1) is present on the surface of B-cells, T-cells, natural killer (NK) cells, dendritic cells, monocytes, and tumor-infiltrating lymphocytes (TILs), while PD-L1 is expressed in cancer cells and APC [31][32]. PD-L1 disrupts intracellular signaling and downregulation of effector T cell function, acting therefore as an immune checkpoint that mediates coinhibitory signals to T cell activation [31]. Cancer cells overexpress PD-1 due to activation of several signaling pathways that are crucial to tumorigenesis. This leads to inhibition of T cell activation, proliferation, and survival and cytotoxic secretion within cancer cells, which promotes induction and maintenance of immune tolerance within the tumor microenvironment [33].

3. Lectins as Decoders of Biological Information in Cellular Glycoconjugates

3.1. Lectins as Tools for N- and O-Glycan Detection and Purification

The capacity of lectins to recognize and bind to specific glycan chains has been historically explored as a tool for the separation and detection of glycans in different analytical techniques. Certain groups of lectins have an affinity for N-linked, O-linked glycoproteins or both types and since they are not species-specific, their spectrum of application is wider than that of antibodies [34].
Lectins are widely used in histochemistry and cytochemistry to detect glycoconjugates in cells and tissues [35]. One way of visualizing lectin-binding sites is an indirect method employing lectins conjugated to a hapten, such as digoxigenin, which is then recognized using enzyme-linked streptavidin [36]. Lectin blotting or lectin-probed Western is a variation of the traditional Western blot, in which lectins are also employed to detect glycoproteins [37]. The lectin blot is very similar to the traditional Western blot, the main difference being that the membrane is then incubated with a specific lectin and labeled with a group, such as digoxigenin (DIG) that will further bind to a secondary antibody conjugated to an enzyme that catalyzes a color-producing reaction (alkaline phosphatase) or a more sensitive luminescence-producing reaction (horseradish peroxidase) [38]. Fluorochrome-labeled lectins can also be used to detect glycans on the cell surface of live cells by flow cytometer [39]. To purify glycoconjugates, lectin affinity chromatography can be applied (LAC). LAC utilizes different immobilized lectins that bind glycoproteins noncovalently and reversibly, and therefore they may be selectively released from an affinity column by competitive elution using a specific corresponding free sugar or sugar analog [40].

3.2. Galectins

Regarding galectins, numerous works have demonstrated this family of lectins is able to influence many events related to assembly of the immune response [41][42][43][44]. Over 15 years ago, outstanding papers published by Rabinovich’s and Baum’s groups were essential to foster the emergence of the glycoimmunology field. Many articles confirmed that galectins, especially galectin-1 (Gal-1), are able to induce the maturation [45], proliferation [46][47] and apoptosis of immune cells [48][49], playing an important role in the development and maintenance of a healthy immune system [18][50][51]. On the subject of T cell biology, at the beginning of the 21st century, with the advancement of glycoimmunology, several papers confirmed that different glycan structures modulate T cell-related biological phenomena, such as activation, differentiation, death, and homing, by either generating or masking ligands for endogenous lectins [52][53][54][55].
Regarding Gal-5, it has been shown to bind to the surface of exosomes secreted by rat reticulocytes, modulating the uptake of vesicles by Mɸ [56]. The differentiation of monocytes to Mɸ may also be modulated by Gal-4, which binds to CD14, triggering the activation of the MAPK signaling pathway [57]. Recently, it was demonstrated that in Mɸ, Gal-8 recognizes damaged Mycobacterium tuberculosis-containing phagosomes, and directs the microorganism to selective autophagy, highlighting the importance of Gal-8 in the innate immune response to this pathogenic bacterium [58]. Some of the effects of different galectins in the immune system are summarized in Figure 2.
/media/item_content/202303/6406d21a1dc7dmedicines-10-00015-g002.png
Figure 2. Differential role of galectins under aspects of immune system function and pathological conditions. Small arrows in blue and red indicate upregulation and downregulation, respectively.

3.3. Siglecs

Siglecs are I-type (immunoglobulin superfamily–type) lectins and exert functions in the immune system in events related to cell adhesion, pathogen recognition, cell activation, signaling, and death, among others [59][60][61][62] (Figure 3). Although many glycan-binding proteins (GBPs) can recognize Sia-containing glycans, siglecs show great specificity for them, forming extensive molecular interactions [59][63][64].

/media/item_content/202303/6406d236ddc54medicines-10-00015-g003.png
Figure 3. Differential role of siglecs during cancer progression. Siglecs expressed in tumor cells and M2 macrophages contribute to protumorigenic effects. Dashed line indicates receptor interaction and dashed arrows indicate successive effects.

4. Oncofetal Antigens as Modulators of the Immune Response

Another topic that has grown exponentially in the field of glycoimmunology is the impact of oncofetal antigens on the immune system [65][66][67][68]. By definition, oncofetal proteins are generated in developing (fetal) as well as cancer (onco) cells. This expression can reproduce essential functions during development that are reactivated during cancer development and/or progression [69]. Usually, oncofetal proteins are decorated with truncated glycans, and many of these are used as glycobiomarkers for the diagnosis of different types of cancer [70]. Examples include the carcinoembryonic antigen [71], the prostate-specific antigen [72], and the CA-125 antigen [73], used as markers for colorectal, prostate, and ovarian cancers, respectively [74]. Usually, oncofetal proteins are able to elicit B cell-dependent immune responses (e.g., antibody production). It is important to note that self-antigens are not immunogenic, and therefore are not capable of inducing the and therefore are not capable of inducing the production of antibodies in an organism said as tolerant [75]. However, oncofetal epitopes are often immunogenic, since they are not widely expressed by adult health cells. In this context, the immune cells may elicit self-immunity under some conditions [76]. Among the unusual glycans carried by oncofetal proteins, Tn sialyl Tn antigens stand out [77][78].
Nowadays, its high expression is known to be associated with a poor prognosis for different types of cancer [79], since it contributes to an immunosuppressive microenvironment and drives molecular pathways associated with metastasis [80]. Preexisting anticarcinoma anti-Tn antibodies are induced mainly by the intestinal flora and normally found in healthy individuals, while cellular immune responses to Tn epitopes are induced only by some lymphomas and carcinomas, in very early, including preclinical, cancer detection [81][82]. Tn antigen can be recognized by the Mɸ galactose/GalNAc lectin, known as MGL, which intermediates numerous immune tolerogenic and regulatory properties, mainly by reprogramming the maturation of dendritic cells [83]. Recently, da Costa and colleagues (2021) demonstrated that the Tn antigen induces the growth of lung tumors by promoting angiogenesis and immunosuppression through its interaction with MGL2 [84] (Figure 4).
/media/item_content/202303/6406d24778266medicines-10-00015-g005.png
Figure 4. Immunomodulatory effects by tumoral antigens. Small arrows in blue indicate upregulation. Dashed line indicates receptor interaction and dashed arrows indicate successive effects.

5. Conclusions

The data collected demonstrate a clear connection between glycobiology and immunology, with glycan epitopes playing a major role in the modulation of the immune system. In addition, the intense modulation dynamics of complex systems and the differential recognition of glycoconjugates also imply changes in recognition and establishment of an immune response. Atypical glycan structures also have great potential as immunotherapy tools for various diseases, and may in the future be used as a scaffold for biotechnological development in the treatment of numerous comorbidities.

References

  1. Esmail, S.; Manolson, M.F. Advances in understanding N-glycosylation structure, function, and regulation in health and disease. Eur. J. Cell Biol. 2021, 100, 151186.
  2. Sun, X.; Zhan, M.; Sun, X.; Liu, W.; Meng, X. C1GALT1 in health and disease (Review). Oncol. Lett. 2021, 22, 589.
  3. Neuberger, A. Carbohydrates in protein: The carbohydrate component of crystalline egg albumin. Biochem. J. 1938, 32, 1435–1451.
  4. Mendonça-Previato, L.; Todeschini, A.R.; Heise, N.; Previato, J.O. Protozoan parasite-specific carbohydrate structures. Curr. Opin. Struct. Biol. 2005, 15, 499–505.
  5. Villena, S.N.; Pinheiro, R.O.; Pinheiro, C.S.; Nunes, M.P.; Takiya, C.M.; DosReis, G.A.; Previato, J.O.; Mendonça-Previato, L.; Freire-De-Lima, C.G. Capsular polysaccharides galactoxylomannan and glucuronoxylomannan from Cryptococcus neoformans induce macrophage apoptosis mediated by Fas ligand. Cell. Microbiol. 2008, 10, 1274–1285.
  6. Dobrica, M.-O.; Lazar, C.; Branza-Nichita, N. N-Glycosylation and N-Glycan Processing in HBV Biology and Pathogenesis. Cells 2020, 9, 1404.
  7. Limoli, D.H.; Jones, C.J.; Wozniak, D.J. Bacterial Extracellular Polysaccharides in Biofilm Formation and Function. Microbiol. Spectr. 2015, 3, 1.
  8. Kumar, A.S.; Mody, K.; Jha, B. Bacterial exopolysaccharides—A perception. J. Basic Microbiol. 2007, 47, 103–117.
  9. Spiro, R.G. Protein glycosylation: Nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds. Glycobiology 2002, 12, 43R–56R.
  10. Wandall, H.H.; Nielsen, M.A.I.; King-Smith, S.; de Haan, N.; Bagdonaite, I. Global functions of O-glycosylation: Promises and challenges in O-glycobiology. FEBS J. 2021, 288, 7183–7212.
  11. Nio-Kobayashi, J. Tissue- and cell-specific localization of galectins, β-galactose-binding animal lectins, and their potential functions in health and disease. Anat. Sci. Int. 2016, 92, 25–36.
  12. Handa, K.; Hakomori, S.-I. Changes of glycoconjugate expression profiles during early development. Glycoconj. J. 2016, 34, 693–699.
  13. Rudd, P.M.; Elliott, T.; Cresswell, P.; Wilson, I.A.; Dwek, R.A. Glycosylation and the Immune System. Science 2001, 291, 2370–2376.
  14. Arnold, J.N.; Dwek, R.A.; Rudd, P.M.; Sim, R.B. Mannan binding lectin and its interaction with immunoglobulins in health and in disease. Immunol. Lett. 2006, 106, 103–110.
  15. Dos Reis, J.S.; Santos, M.A.R.D.C.; Mendonça, D.P.; Nascimento, S.I.M.D.; Barcelos, P.M.; de Lima, R.G.C.; da Costa, K.M.; Freire-De-Lima, C.G.; Morrot, A.; Previato, J.O.; et al. Glycobiology of Cancer: Sugar Drives the Show. Medicines 2022, 9, 34.
  16. Reily, C.; Stewart, T.J.; Renfrow, M.B.; Novak, J. Glycosylation in health and disease. Nat. Rev. Nephrol. 2019, 15, 346–366.
  17. Schjoldager, K.T.; Narimatsu, Y.; Joshi, H.J.; Clausen, H. Global view of human protein glycosylation pathways and functions. Nat. Rev. Mol. Cell Biol. 2020, 21, 729–749.
  18. Rabinovich, G.A.; Toscano, M.A.; Jackson, S.S.; Vasta, G.R. Functions of cell surface galectin-glycoprotein lattices. Curr. Opin. Struct. Biol. 2007, 17, 513–520.
  19. Elola, M.T.; Blidner, A.G.; Ferragut, F.; Bracalente, C.; Rabinovich, G.A. Assembly, organization and regulation of cell-surface receptors by lectin–glycan complexes. Biochem. J. 2015, 469, 1–16.
  20. Baum, L.G.; Cobb, B.A. The direct and indirect effects of glycans on immune function. Glycobiology 2017, 27, 619–624.
  21. Munkley, J.; Elliott, D.J. Hallmarks of glycosylation in cancer. Oncotarget 2016, 7, 35478–35489.
  22. Taniguchi, N.; Kizuka, Y. Glycans and Cancer: Role of N-glycans in cancer biomarker, progression and metastasis, and therapeutics. Adv. Cancer Res. 2015, 126, 11–51.
  23. Nagae, M.; Kizuka, Y.; Mihara, E.; Kitago, Y.; Hanashima, S.; Ito, Y.; Takagi, J.; Taniguchi, N.; Yamaguchi, Y. Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V. Nat. Commun. 2018, 9, 3380.
  24. Dhatchinamoorthy, K.; Colbert, J.D.; Rock, K.L. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Front. Immunol. 2021, 12, 636568.
  25. Dong, H.; Strome, S.E.; Salomao, D.R.; Tamura, H.; Hirano, F.; Flies, D.B.; Roche, P.C.; Lu, J.; Zhu, G.; Tamada, K.; et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat. Med. 2002, 8, 793–800.
  26. Nardy, A.F.F.R.; Freire-De-Lima, L.; Freire-De-Lima, C.G.; Morrot, A. The Sweet Side of Immune Evasion: Role of Glycans in the Mechanisms of Cancer Progression. Front. Oncol. 2016, 6, 54.
  27. Silva, M.C.; Fernandes, A.; Oliveira, M.; Resende, C.; Correia, A.; De-Freitas-Junior, J.C.M.; Lavelle, A.; Andrade-Da-Costa, J.; Leander, M.; Xavier-Ferreira, H.; et al. Glycans as Immune Checkpoints: Removal of Branched N-glycans Enhances Immune Recognition Preventing Cancer Progression. Cancer Immunol. Res. 2020, 8, 1407–1425.
  28. Grigorian, A.; Demetriou, M. Mgat5 Deficiency in T Cells and Experimental Autoimmune Encephalomyelitis. ISRN Neurol. 2011, 2011, 374314.
  29. Lee, S.-U.; Grigorian, A.; Pawling, J.; Chen, I.-J.; Gao, G.; Mozaffar, T.; McKerlie, C.; Demetriou, M. N-Glycan Processing Deficiency Promotes Spontaneous Inflammatory Demyelination and Neurodegeneration. J. Biol. Chem. 2007, 282, 33725–33734.
  30. Pereira, M.S.; Alves, I.; Vicente, M.; Campar, A.; Silva, M.C.; Padrão, N.; Pinto, V.; Fernandes, A.; Dias, A.; Pinho, S.S. Glycans as Key Checkpoints of T Cell Activity and Function. Front. Immunol. 2018, 9, 2754.
  31. Ghosh, C.; Luong, G.; Sun, Y. A snapshot of the PD-1/PD-L1 pathway. J. Cancer 2021, 12, 2735–2746.
  32. Su, C.; Wang, H.; Liu, Y.; Guo, Q.; Zhang, L.; Li, J.; Zhou, W.; Yan, Y.; Zhou, X.; Zhang, J. Adverse Effects of Anti-PD-1/PD-L1 Therapy in Non-small Cell Lung Cancer. Front. Oncol. 2020, 10, 554313.
  33. Han, Y.; Liu, D.; Li, L. PD-1/PD-L1 pathway: Current researches in cancer. Am. J. Cancer Res. 2020, 10, 727–742.
  34. Akimoto, Y.; Kawakami, H. Histochemical Staining Using Lectin Probes. Methods Mol. Biol. 2014, 1200, 153–163.
  35. Stoddart, R.W.; Jones, C.J.P. Lectin Histochemistry and Cytochemistry-Light Microscopy: Avidin-Biotin Amplification on Resin- Embedded Sectlons. Methods Mol. Biol. 1998, 9, 21–40.
  36. Hashim, O.H.; Jayapalan, J.J.; Lee, C.-S. Lectins: An effective tool for screening of potential cancer biomarkers. Peerj 2017, 5, e3784.
  37. Sato, T. Lectin-Probed Western Blot Analysis. Methods Mol. Biol. 2014, 1200, 93–100.
  38. Roth, Z.; Yehezkel, G.; Khalaila, I. Identification and Quantification of Protein Glycosylation. Int. J. Carbohydr. Chem. 2012, 2012, 10.
  39. Moriwaki, K.; Miyoshi, E. Basic Procedures for Lectin Flow Cytometry. Methods Mol. Biol. 2014, 1200, 147–152.
  40. Goumenou, A.; Delaunay, N.; Pichon, V. Recent Advances in Lectin-Based Affinity Sorbents for Protein Glycosylation Studies. Front. Mol. Biosci. 2021, 8, 746822.
  41. Nishi, N.; Shoji, H.; Seki, M.; Itoh, A.; Miyanaka, H.; Yuube, K.; Hirashima, M.; Nakamura, T. Galectin-8 modulates neutrophil function via interaction with integrin M. Glycobiology 2003, 13, 755–763.
  42. Heyl, K.A.; Karsten, C.M.; Slevogt, H. Galectin-3 binds highly galactosylated IgG1 and is crucial for the IgG1 complex mediated inhibition of C5aReceptor induced immune responses. Biochem. Biophys. Res. Commun. 2016, 479, 86–90.
  43. Giovannone, N.; Smith, L.K.; Treanor, B.; Dimitroff, C.J. Galectin-Glycan Interactions as Regulators of B Cell Immunity. Front. Immunol. 2018, 9, 2839.
  44. Vasta, G.R.; Quesenberry, M.; Ahmed, H.; O’Leary, N. C-type lectins and galectins mediate innate and adaptive immune functions: Their roles in the complement activation pathway. Dev. Comp. Immunol. 1999, 23, 401–420.
  45. Baum, L.G.; Pang, M.; Perillo, N.L.; Wu, T.; Delegeane, A.; Uittenbogaart, C.H.; Fukuda, M.; Seilhamer, J.J. Human thymic epithelial cells express an endogenous lectin, galectin-1, which binds to core 2 O-glycans on thymocytes and T lymphoblastoid cells. J. Exp. Med. 1995, 181, 877–887.
  46. Manzi, M.; Bacigalupo, M.L.; Carabias, P.; Elola, M.T.; Wolfenstein-Todel, C.; Rabinovich, G.A.; Espelt, M.V.; Troncoso, M.F. Galectin-1 Controls the Proliferation and Migration of Liver Sinusoidal Endothelial Cells and Their Interaction with Hepatocarcinoma Cells. J. Cell. Physiol. 2015, 231, 1522–1533.
  47. Perillo, N.L.; Marcus, M.E.; Baum, L.G. Galectins: Versatile modulators of cell adhesion, cell proliferation, and cell death. J. Mol. Med. 1998, 76, 402–412.
  48. Earl, L.A.; Bi, S.; Baum, L.G. N- and O-Glycans Modulate Galectin-1 Binding, CD45 Signaling, and T Cell Death. J. Biol. Chem. 2010, 285, 2232–2244.
  49. Zuñiga, E.; Rabinovich, G.A.; Iglesias, M.M.; Gruppi, A. Regulated expression of galectin-1 during B-cell activation and implications for T-cell apoptosis. J. Leukoc. Biol. 2001, 70, 73–79.
  50. Blidner, A.G.; Méndez-Huergo, S.P.; Cagnoni, A.J.; Rabinovich, G.A. Re-wiring regulatory cell networks in immunity by galectin-glycan interactions. FEBS Lett. 2015, 589, 3407–3418.
  51. Thiemann, S.; Baum, L.G. Galectins and Immune Responses—Just How Do They Do Those Things They Do? Annu. Rev. Immunol. 2016, 34, 243–264.
  52. Toscano, M.A.; Bianco, G.A.; Ilarregui, J.M.; Croci, D.O.; Correale, J.; Hernandez, J.D.; Zwirner, N.; Poirier, F.; Riley, E.M.; Baum, L.G.; et al. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat. Immunol. 2007, 8, 825–834.
  53. Rabinovich, G.A.; Ilarregui, J.M. Conveying glycan information into T-cell homeostatic programs: A challenging role for galectin-1 in inflammatory and tumor microenvironments. Immunol. Rev. 2009, 230, 144–159.
  54. Sotomayor, C.E.; Rabinovich, G.A. Galectin-1 Induces Central and Peripheral Cell Death: Implications in T-Cell Physiopathology. Dev. Immunol. 2000, 7, 117–129.
  55. Cooper, D.; Ilarregui, J.M.; Pesoa, S.A.; Croci, D.O.; Perretti, M.; Rabinovich, G.A. Multiple Functional Targets of the Immunoregulatory Activity of Galectin-1: Control of immune cell trafficking, dendritic cell physiology, and T-cell fate. Methods Enzym. 2010, 480, 199–244.
  56. Barrès, C.; Blanc, L.; Bette-Bobillo, P.; André, S.; Mamoun, R.; Gabius, H.-J.; Vidal, M. Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood 2010, 115, 696–705.
  57. Hong, S.-H.; Shin, J.-S.; Chung, H.; Park, C.-G. Galectin-4 Interaction with CD14 Triggers the Differentiation of Monocytes into Macrophage-like Cells via the MAPK Signaling Pathway. Immune Netw. 2019, 19, e17.
  58. Bell, S.L.; Lopez, K.L.; Cox, J.S.; Patrick, K.L.; Watson, R.O. Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control Mycobacterium tuberculosis Infection in Macrophages. Mbio 2021, 12, e0187120.
  59. Bochner, B.S.; Zimmermann, N. Role of siglecs and related glycan-binding proteins in immune responses and immunoregulation. J. Allergy Clin. Immunol. 2015, 135, 598–608.
  60. Murugesan, G.; Weigle, B.; Crocker, P.R. Siglec and anti-Siglec therapies. Curr. Opin. Chem. Biol. 2021, 62, 34–42.
  61. Gonzalez-Gil, A.; Schnaar, R.L. Siglec Ligands. Cells 2021, 10, 1260.
  62. Van Houtum, E.J.H.; Büll, C.; Cornelissen, L.A.M.; Adema, G.J. Siglec Signaling in the Tumor Microenvironment. Front. Immunol. 2021, 12, 790317.
  63. Smith, B.A.H.; Bertozzi, C.R. The clinical impact of glycobiology: Targeting selectins, Siglecs and mammalian glycans. Nat. Rev. Drug Discov. 2021, 20, 217–243.
  64. Duan, S.; Paulson, J.C. Siglecs as Immune Cell Checkpoints in Disease. Annu. Rev. Immunol. 2020, 38, 365–395.
  65. Sharma, A.; Seow, J.J.W.; Dutertre, C.-A.; Pai, R.; Blériot, C.; Mishra, A.; Wong, R.M.M.; Singh, G.S.N.; Sudhagar, S.; Khalilnezhad, S.; et al. Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma. Cell 2020, 183, 377–394.e21.
  66. Li, D.; Li, N.; Zhang, Y.-F.; Fu, H.; Feng, M.; Schneider, D.; Su, L.; Wu, X.; Zhou, J.; Mackay, S.; et al. Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice. Gastroenterology 2020, 158, 2250–2265.e20.
  67. Sun, C.; Lan, P.; Han, Q.; Huang, M.; Zhang, Z.; Xu, G.; Song, J.; Wang, J.; Wei, H.; Zhang, J.; et al. Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion. Nat. Commun. 2018, 9, 1241.
  68. Elcheva, I.A.; Wood, T.; Chiarolanzio, K.; Chim, B.; Wong, M.; Singh, V.; Gowda, C.P.; Lu, Q.; Hafner, M.; Dovat, S.; et al. RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1. Leukemia 2020, 34, 1354–1363.
  69. Stern, P.L. Oncofetal Antigen. In Encyclopedia of Cancer; Schwab, M., Ed.; Springer: Berlin/Heidelberg, Germany, 2011; pp. 2610–2613.
  70. Buonaguro, F.M.; Pauza, D.; Tornesello, M.L.; Hainaut, P.; Franco, R.; Marincola, F.M. Cancer Diagnostic and Predictive Biomarkers. BioMed Res. Int. 2014, 2014, 980163.
  71. Drake, P.M.; Cho, W.; Li, B.; Prakobphol, A.; Johansen, E.; Anderson, N.L.; Regnier, F.E.; Gibson, B.W.; Fisher, S.J. Sweetening the Pot: Adding Glycosylation to the Biomarker Discovery Equation. Clin. Chem. 2010, 56, 223–236.
  72. Peracaula, R.; Tabarés, G.; Royle, L.; Harvey, D.J.; Dwek, R.A.; Rudd, P.M.; de Llorens, R.R. Altered glycosylation pattern allows the distinction between prostate-specific antigen (PSA) from normal and tumor origins. Glycobiology 2003, 13, 457–470.
  73. Saldova, R.; Struwe, W.B.; Wynne, K.; Elia, G.; Duffy, M.J.; Rudd, P.M. Exploring the Glycosylation of Serum CA125. Int. J. Mol. Sci. 2013, 14, 15636–15654.
  74. Freire-De-Lima, L. Sweet and sour: The impact of differential glycosylation in cancer cells undergoing epithelial-mesenchymal transition. Front. Oncol. 2014, 4, 59.
  75. Backes, C.; Ludwig, N.; Leidinger, P.; Harz, C.; Hoffmann, J.; Keller, A.; Meese, E.; Lenhof, H.-P. Immunogenicity of autoantigens. BMC Genom. 2011, 12, 340.
  76. McClintock, S.D.; Warner, R.L.; Ali, S.; Chekuri, A.; Dame, M.K.; Attili, D.; Knibbs, R.K.; Aslam, M.N.; Sinkule, J.; Morgan, A.C.; et al. Monoclonal antibodies specific for oncofetal antigen—Immature laminin receptor protein: Effects on tumor growth and spread in two murine models. Cancer Biol. Ther. 2015, 16, 724–732.
  77. Fu, C.; Zhao, H.; Wang, Y.; Cai, H.; Xiao, Y.; Zeng, Y.; Chen, H. Tumor-associated antigens: Tn antigen, sTn antigen, and T antigen. Hla 2016, 88, 275–286.
  78. Bulteau, F.; Thépaut, M.; Henry, M.; Hurbin, A.; Vanwonterghem, L.; Vivès, C.; Le Roy, A.; Ebel, C.; Renaudet, O.; Fieschi, F.; et al. Targeting Tn-Antigen-Positive Human Tumors with a Recombinant Human Macrophage Galactose C-Type Lectin. Mol. Pharm. 2021, 19, 235–245.
  79. Ju, T.; Wang, Y.; Aryal, R.P.; Lehoux, S.D.; Ding, X.; Kudelka, M.R.; Cutler, C.; Zeng, J.; Wang, J.; Sun, X.; et al. Tn and sialyl-Tn antigens, aberrant O-glycomics as human disease markers. Proteom. Clin. Appl. 2013, 7, 618–631.
  80. Cornelissen, L.A.M.; Blanas, A.; Zaal, A.; Van Der Horst, J.C.; Kruijssen, L.J.W.; O’Toole, T.; Van Kooyk, Y.; Van Vliet, S.J. Tn Antigen Expression Contributes to an Immune Suppressive Microenvironment and Drives Tumor Growth in Colorectal Cancer. Front. Oncol. 2020, 10, 1622.
  81. Springer, G.F. Immunoreactive T and Tn epitopes in cancer diagnosis, prognosis, and immunotherapy. J. Mol. Med. 1997, 75, 594–602.
  82. Desai, P.R. Immunoreactive T and Tn antigens in malignancy: Role in carcinoma diagnosis, prognosis, and immunotherapy. Transfus. Med. Rev. 2000, 14, 312–325.
  83. Da Costa, V.; Mariño, K.V.; Rodríguez-Zraquia, S.A.; Festari, M.F.; Lores, P.; Costa, M.; Landeira, M.; Rabinovich, G.A.; van Vliet, S.J.; Freire, T. Lung Tumor Cells with Different Tn Antigen Expression Present Distinctive Immunomodulatory Properties. Int. J. Mol. Sci. 2022, 23, 12047.
  84. Da Costa, V.; van Vliet, S.J.; Carasi, P.; Frigerio, S.; García, P.A.; Croci, D.O.; Festari, M.F.; Costa, M.; Landeira, M.; Rodríguez-Zraquia, S.A.; et al. The Tn antigen promotes lung tumor growth by fostering immunosuppression and angiogenesis via interaction with Macrophage Galactose-type lectin 2 (MGL2). Cancer Lett. 2021, 518, 72–81.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology; Infectious Diseases
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Jhenifer Santos dos Reis
,
Israel Diniz-Lima
,
Marcos André Rodrigues da Costa Santos
,
Pedro Marçal Barcelos
,
Kelli Monteiro da Costa
,
Raphael do Carmo Valente
,
Lorrane de Souza Chaves
,
Luma Petel de Campos
,
Ariely Costa dos Santos
,
Rafaela Gomes Correia de Lima
,
Debora Decote-Ricardo
,
Alexandre Morrot
,
Jose Osvaldo Previato
,
Lucia Mendonça-Previato
,
Celio Geraldo Freire-de-Lima
,
Leonardo Marques da Fonseca
,
Leonardo Freire-de-Lima
View Times: 628
Revisions: 2 times (View History)
Update Date: 07 Mar 2023
Table of Contents
Video Production Service
Feedback