Advances in the Immunomodulatory Properties of Glycoantigens in Cancer

Abstract

Aberrant glycosylation in tumour progression is currently a topic of main interest. Tumour-associated carbohydrate antigens (TACAs) are expressed in a wide variety of epithelial cancers, being both a diagnostic tool and a potential treatment target, as they have impact on patient outcome and disease progression. Glycans affect both tumour-cell biology properties as well as the antitumor immune response. It has been ascertained that TACAs affect cell migration, invasion and metastatic properties both when expressed by cancer cells or by their extracellular vesicles. On the other hand, tumour-associated glycans recognized by C-type lectin receptors in immune cells possess immunomodulatory properties which enable tumour growth and immune response evasion. Yet, much remains unknown, concerning mechanisms involved in deregulation of glycan synthesis and how this affects cell biology on a major level. This review summarises the main findings to date concerning how aberrant glycans influence tumour growth and immunity, their application in cancer treatment and spotlights of unanswered challenges remaining to be solved.

The transcriptional landscape of glycosylation-related genes in cancer

“…Given that several tumor-associated glycans have been associated with the induction of a tolerogenic microenvironment, the identification of specific GRGs and GRPs can aid to better understand glycanmediated regulatory programs in cancer 2,38 . Gastro-intestinal cancers are highly enriched in the expression of fucosyltransferases responsible for the synthesis of Lewis antigens, suggesting that these tumor types may be particularly affected by the fucose-specific immunomodulatory receptor DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin).…”

“…Alterations in tumor glycosylation can be the result of multiple mechanisms other than the expression of GRGs, including changes in localization of glycosyltransferases or differences in chaperone function 64 . The Tn antigen, one of the most studies glycan structures in cancer, corresponds to the first step of the mucin-type Oglycosylation: a simple N-Acetyl-galactosamine bound to a serine, threonine o tyrosine in the peptide backbone of a protein 2,38,65,66 . Its synthesis is catalyzed by a family of twenty enzymes called polypeptide N-Acetylgalactosaminyltransferase (encoded by the genes GALNT) that differ in their tissue distribution and specificity 67,68 .…”

“…Alterations in tumor glycosylation can be the result of multiple mechanisms other than the expression of GRGs, including changes in localization of glycosyltransferases or differences in chaperone function 64 . The Tn antigen, one of the most studies glycan structures in cancer, corresponds to the first step of the mucin-type O -glycosylation: a simple N -Acetyl-galactosamine bound to a serine, threonine o tyrosine in the peptide backbone of a protein 2,38,65,66 Its synthesis is catalyzed by a family of twenty enzymes called polypeptide N -Acetylgalactosaminyltransferase (encoded by the genes GALNT ) that differ in their tissue distribution and specificity 67,68. However, their presence in tumor cells is difficult to predict based only on transcriptomic analysis as it can be influenced by multiple factors: activity or defects of the extending enzymes (C1GALT1 and ST6GALNAC1) or the COSMC chaperone (C1GALT1C1), overexpression of carriers (like mucins) and GALNT re-localization to the endoplasmic reticulum 69-71 .…”

Lung Tumor Cells with Different Tn Antigen Expression Present Distinctive Immunomodulatory Properties

“…Lung cancer is the first world leading cause of cancer-related deaths for both men and women [ 1 , 2 ]. Aberrant glycosylation is a hallmark of epithelial tumors [ 3 ], including lung cancer [ 4 , 5 ]. Altered glycosylation pathways of tumors lead to the expression of tumor-associated carbohydrate antigens [ 3 ], such as the Tn antigen, which is highly expressed by adenocarcinomas [ 6 ].…”

“…Aberrant glycosylation is a hallmark of epithelial tumors [ 3 ], including lung cancer [ 4 , 5 ]. Altered glycosylation pathways of tumors lead to the expression of tumor-associated carbohydrate antigens [ 3 ], such as the Tn antigen, which is highly expressed by adenocarcinomas [ 6 ]. Tn antigen is associated with cancer aggressiveness, poor prognosis, and metastasis [ 6 , 7 ].…”