Sialyl Tn‐expressing bladder cancer cells induce a tolerogenic phenotype in innate and adaptive immune cells

Carrascal, Mylène A.; Severino, Paulo F.; Cabral, M. Guadalupe; Silva, Mariana; Ferreira, José Alexandre; Calais, Fernando; Quinto, Hermínia; Pen, Cláudia; Ligeiro, Dário; Santos, Lúcio Lara; Dall’Olio, Fabio; Videira, Paula A.

doi:10.1016/j.molonc.2014.02.008

Cited by 95 publications

(101 citation statements)

References 47 publications

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“…Key strategic issues included the removal of the acetyl esters of the glycan moiety prior to the installation of the Pam 2 CysFmoc moiety, the use of a strategically chosen STn building block that has the carboxylic acid of the sialoside protected as an allyl ester which could be removed under neutral conditions without causing β-elimination of the O -glycan, and microwave-assisted solid-phase peptide. Although it has been suggested that STn can suppress immune responses, 26 we have found that a fully synthetic three-component vaccine containing this epitope can elicit potent humoral as well cellular immune responses. Furthermore, it is shown that T-cells primed by such a vaccine can be restimulated by tumor-associated MUC1, which is highly significant because such restimulation of T-cells will lead to their expansion at the site of the tumor and be more able to eliminate cancer cells.…”

mentioning

confidence: 58%

Linear synthesis and immunological properties of a fully synthetic vaccine candidate containing a sialylated MUC1 glycopeptide

et al. 2015

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mentioning

confidence: 58%

Linear synthesis and immunological properties of a fully synthetic vaccine candidate containing a sialylated MUC1 glycopeptide

et al. 2015

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“…Monocytes were enriched using anti-CD14 mAb-coated immunomagnetic beads and cultured, as described previously. [24]…”

Section: Methodsmentioning

confidence: 99%

Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses

Silva

Marques

et al. 2016

Oncotarget

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Dendritic cells (DCs) hold promise for anti-cancer immunotherapy. However, clinically, their efficiency is limited and novel strategies to improve DC-mediated anti-tumor responses are needed. Human DCs display high content of sialic acids, which inhibits their maturation and co-stimulation capacity. Here, we aimed to understand whether exogenous desialylation of DCs improves their anti-tumor immunity. Compared to fully sialylated DCs, desialylated human DCs loaded with tumor-antigens showed enhanced ability to induce autologous T cells to proliferate, to secrete Th1 cytokines, and to specifically induce tumor cell apoptosis. Desialylated DCs showed an increased expression of MHC-I and -II, co-stimulatory molecules and an augmented secretion of IL-12. Desialylated HLA-A*02:01 DCs pulsed with gp100 peptides displayed enhanced peptide presentation through MHC-I, resulting in higher activation ofgp100280–288 specific CD8+ cytotoxic T cells. Desialylated murine DCs also exhibited increased MHC and co-stimulatory molecules and higher antigen cross-presentation via MHC-I. These DCs showed higher ability to activate antigen-specific CD4+ and CD8+ T cells, and to specifically induce tumor cell apoptosis. Collectively, our data demonstrates that desialylation improves DCs' ability to elicit T cell-mediated anti-tumor activity, due to increased MHC-I expression and higher antigen presentation via MHC-I. Sialidase treatment of DCs may represent a technology to improve the efficacy of antigen loaded-DC-based vaccines for anti-cancer immunotherapy.

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“…We have previously proposed that the exceptional avidity of binding between the tandemly repeated carbohydrates of MUC1 and mannose receptors on DC does not allow their dissociation after cellular internalization and thereby MUC1 degradation [95]. It was also observed that STn+ cancer cells inhibited generation of Th1 T cells further, limiting the ability of the anti-tumor T cell response [96]. This all affects development of stronger anti-MUC1 immunity that could otherwise target the abnormal MUC1 as an antigen on tumor cells for efficient cancer immunosurveillance.…”

Section: Abnormal Muc1 In the Tumor Microenvironmentmentioning

confidence: 99%

Intra- and Extra-Cellular Events Related to Altered Glycosylation of MUC1 Promote Chronic Inflammation, Tumor Progression, Invasion, and Metastasis

Cascio

Finn

2016

Biomolecules

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Altered glycosylation of mucin 1 (MUC1) on tumor cells compared to normal epithelial cells was previously identified as an important antigenic modification recognized by the immune system in the process of tumor immunosurveillance. This tumor form of MUC1 is considered a viable target for cancer immunotherapy. The importance of altered MUC1 glycosylation extends also to its role as a promoter of chronic inflammatory conditions that lead to malignant transformation and cancer progression. We review here what is known about the role of specific cancer-associated glycans on MUC1 in protein-protein interactions and intracellular signaling in cancer cells and in their adhesion to each other and the tumor stroma. The tumor form of MUC1 also creates a different landscape of inflammatory cells in the tumor microenvironment by controlling the recruitment of inflammatory cells, establishing specific interactions with dendritic cells (DCs) and macrophages, and facilitating tumor escape from the immune system. Through multiple types of short glycans simultaneously present in tumors, MUC1 acquires multiple oncogenic properties that control tumor development, progression, and metastasis at different steps of the process of carcinogenesis.

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Sialyl Tn‐expressing bladder cancer cells induce a tolerogenic phenotype in innate and adaptive immune cells

Cited by 95 publications

References 47 publications

Linear synthesis and immunological properties of a fully synthetic vaccine candidate containing a sialylated MUC1 glycopeptide

Linear synthesis and immunological properties of a fully synthetic vaccine candidate containing a sialylated MUC1 glycopeptide

Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses

Intra- and Extra-Cellular Events Related to Altered Glycosylation of MUC1 Promote Chronic Inflammation, Tumor Progression, Invasion, and Metastasis

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