The Tn antigen promotes lung tumor growth by fostering immunosuppression and angiogenesis via interaction with Macrophage Galactose-type lectin 2 (MGL2)

Costa, Valeria da; Vliet, Sandra J. van; Carasi, Paula; Frigerio, Sofía; García, Pablo Andrés; Croci, Diego O.; Festari, María Florencia; Costa, Monique; Landeira, Mercedes; Rodríguez-Zraquia, Santiago A.; Cagnoni, Alejandro J.; Cutine, Anabela María; Rabinovich, Gabriel A.; Osinaga, Eduardo; Mariño, Karina; Freire, Teresa

doi:10.1016/j.canlet.2021.06.012

Cited by 26 publications

(31 citation statements)

References 48 publications

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Section: Discussionmentioning

confidence: 99%

“…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 .…”

Section: Discussionmentioning

confidence: 99%

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The transcriptional landscape of glycosylation-related genes in cancer

Rodríguez

Lindijer

Vliet

et al. 2022

Preprint

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Changes in glycosylation patterns have been associated with malignant transformation and clinical outcome in several types of cancer, although no comprehensive analysis has been performed in a pan-cancer setting. Here, we performed an extensive transcriptomic analysis of glycosylation related genes (such as enzymes involved in synthesis and degradation of glycoconjugates, transporters, mucins and galectins), using publicly available bulk and single cell transcriptomic data sets from tumor samples and cancer cell lines. We identified genes and pathways associated with different tumor types, which may represent novel diagnostic biomarkers as α2-3 sialylation for Melanoma, MUC21 for Lung adenocarcinoma and Galectin-7 for Squamous cell carcinomas (SCC). Accordingly, serum levels of Galectin-7 in patients with lung cancer were elevated in SCC respect to adenocarcinomas, supporting its biomarker potential. Moreover, we characterized the contribution of different cell types to the overall glycosylation profiles observed by performing the integration and analysis of 14 single cell RNA-seq datasets. This led us to identify that cancer cells are responsible for the specific tumor glyco-codes identified in bulk transcriptomics, while stromal and immune cells contribute in a conserved manner across various malignancies. Furthermore, our results suggest that the glycosylation-related genes and pathways expressed by cancer cells are influenced by the cell of origin and the oncogenic pathways that led to malignant transformation. Lastly, we described the association of different glycosylation-related genes and pathways with the clinical outcome of patients. Interestingly, while the expression of genes associated to some pathways (as proteoglycan biosynthesis) are consistently associated with a more aggressive disease, the correlation of others pathways with the survival of patients depends on the particular tumor type. Remarkably, the expression of genes associated with the synthesis of CMP-sialic acid was correlated with lower survival of patients in Uveal Melanoma and PDAC, while the opposite was observed for colorectal cancer. The extensive transcriptomic analysis of glycosylation pathways in cancer that we report here can serve as a resource for future research aimed to unravel the glyco-code in cancer related to clinical outcome or biomarker development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The transcriptional landscape of glycosylation-related genes in cancer

Rodríguez

Lindijer

Vliet

et al. 2022

Preprint

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“…The Tn antigen is recognized by antigen-presenting cells (dendritic cells and macrophages), leading to the activation of complex immune responses. On the one hand, the administration of glycan-based therapies has been suggested for anticancer vaccination. , On the other hand, recognition of Tn-positive tumor cells by immune cells may result in immunosuppression, , by promoting Treg cell differentiation and favoring suppression of T cell activation. Exogenously administered purified MGL could thus be used to compete and reduce the binding of dendritic cells on the Tn-expressing tumor cells, and thus reducing tumor escape.…”

Section: Discussionmentioning

confidence: 99%

Targeting Tn-Antigen-Positive Human Tumors with a Recombinant Human Macrophage Galactose C-Type Lectin

et al. 2021

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Alterations in glycosylation cause the emergence of tumor-associated carbohydrate antigens (TACAs) during tumorigenesis. Truncation of O-glycans reveals the Thomsen nouveau (Tn) antigen, an N-acetylgalactosamine (GalNAc) frequently attached to serine or threonine amino acids, that is accessible on the surface of cancer cells but not on healthy cells. Interestingly, GalNac can be recognized by macrophage galactose lectin (MGL), a type C lectin receptor expressed in immune cells. In this study, recombinant MGL fragments were tested in vitro for their cancer cell-targeting efficiency by flow cytometry and confocal microscopy and in vivo after administration of fluorescent MGL to tumor-bearing mice. Our results demonstrate the ability of MGL to target Tn-positive human tumors without inducing toxicity. This outcome makes MGL, a fragment of a normal human protein, the first vector candidate for in vivo diagnosis and imaging of human tumors and, possibly, for therapeutic applications.

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“…However, the Tn antigen, besides inducing antitumor immune response, can also favor tumor immune tolerance, explaining at least in part the failure of some vaccine strategies. For example, Tn is recognized by the tolerogenic lectin-macrophage galactose C-type lectin (MGL)-expressed by dendritic cells and macrophages, which allows these cells to suppress T cell immunity [195] and promote angiogenesis [196], thus playing a role in cancer progression. In addition, overexpression of Tn antigen in mouse MC38 colorectal cancer cells increased myeloid-derived suppressor cells and decreased CD8+ T cell infiltration, promoting an immune-suppressive tumor microenvironment [197].…”

Section: Tn Antigenmentioning

confidence: 99%

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Berois

Pittini

Osinaga

2022

Cancers

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Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.

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The Tn antigen promotes lung tumor growth by fostering immunosuppression and angiogenesis via interaction with Macrophage Galactose-type lectin 2 (MGL2)

Cited by 26 publications

References 48 publications

The transcriptional landscape of glycosylation-related genes in cancer

The transcriptional landscape of glycosylation-related genes in cancer

Targeting Tn-Antigen-Positive Human Tumors with a Recombinant Human Macrophage Galactose C-Type Lectin

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

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