Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance

Sørensen, Anne Louise; Reis, Celso A.; Tarp, Mads A.; Mandel, Ulla; Ramachandran, K.; Sankaranarayanan, Vasanthi; Schwientek, Tilo; Graham, Ros; Taylor‐Papadimitriou, Joyce; Hollingsworth, Michael A.; Burchell, Joy; Clausen, Henrik

doi:10.1093/glycob/cwj044

Cited by 233 publications

(220 citation statements)

References 46 publications

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“…rST-MUC1 exerts immunosuppressing effects on dendritic cell differentiation (32), promotes tumor growth (33), and no IgG specific response against the ST-MUC1 glycoform was detected in patients with cancer (34). On the other hand, Tn-MUC1 is immunogenic in mouse models (17,20) and is a target of a specific IgG immune response in patients with cancer (5). Despite the different immunogenicity, both rST-MUC1 and rTn-MUC1 were accumulated mostly in the endolysosomal compartment of iDCs after endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Microvesicle Cargo of Tumor-Associated MUC1 to Dendritic Cells Allows Cross-presentation and Specific Carbohydrate Processing

Rughetti

Rahimi

Belleudi

et al. 2014

Cancer Immunology Research

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Tumor-associated glycoproteins are a group of antigens with high immunogenic interest: The glycoforms generated by the aberrant glycosylation are tumor-specific and the novel glycoepitopes exposed can be targets of tumor-specific immune responses. The MUC1 antigen is one of the most relevant tumor-associated glycoproteins. In cancer, MUC1 loses polarity and becomes overexpressed and hypoglycosylated. Changes in glycan moieties contribute to MUC1 immunogenicity and can modify the interactions of tumor cells with antigen-presenting cells such as dendritic cells that would affect the overall antitumor immune response. Here, we show that the form of the MUC1 antigen, i.e., soluble or as microvesicle cargo, influences MUC1 processing in dendritic cells. In fact, MUC1 carried by microvesicles translocates from the endolysosomal/HLA-II to the HLA-I compartment and is presented by dendritic cells to MUC1-specific CD8 þ T cells stimulating IFN-g responses, whereas the soluble MUC1 is retained in the endolysosomal/HLA-II compartment independently by the glycan moieties and by the modality of internalization (receptor-mediated or non-receptor mediated). MUC1 translocation to the HLA-I compartment is accompanied by deglycosylation that generates novel MUC1 glycoepitopes. Microvesicle-mediated transfer of tumor-associated glycoproteins to dendritic cells may be a relevant biologic mechanism in vivo contributing to define the type of immunogenicity elicited. Furthermore, these results have important implications for the design of glycoprotein-based immunogens for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Microvesicle Cargo of Tumor-Associated MUC1 to Dendritic Cells Allows Cross-presentation and Specific Carbohydrate Processing

Rughetti

Rahimi

Belleudi

et al. 2014

Cancer Immunology Research

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“…Changes in O-glycosylation are a hallmark of cancer cells, and immunogenic short immature aberrant O-glycans are termed pan-carcinoma antigens (60). Our interest in engineering O-glycosylation from scratch stems from our previous identification of immunodominant aberrant O-glycopeptide epitopes in the cancer-associated MUC1 mucin, which are not covered by immunological tolerance (41,61,62). Vaccination with MUC1 glycopeptides with the truncated GalNAc-Ser/Thr O-glycoform produced by GalNAc-T2 and -T4 in combination produce IgG antibodies with cancer-specific reactivity (61), and spontaneous IgG antibodies to the same epitope are found in many cancer patients at time of diagnosis (3,63).…”

Section: Discussionmentioning

confidence: 99%

Engineering Mammalian Mucin-type O-Glycosylation in Plants

Yang

Drew

Jørgensen

et al. 2012

Journal of Biological Chemistry

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Mucin-type O-glycosylation is an important post-translational modification that confers a variety of biological properties and functions to proteins. This post-translational modification has a particularly complex and differentially regulated biosynthesis rendering prediction and control of where O-glycans are attached to proteins, and which structures are formed, difficult. Because plants are devoid of GalNAc-type O-glycosylation, we have assessed requirements for establishing human GalNAc O-glycosylation de novo in plants with the aim of developing cell systems with custom-designed O-glycosylation capacity. Transient expression of a Pseudomonas aeruginosa Glc(NAc) C4-epimerase and a human polypeptide GalNAc-transferase in leaves of Nicotiana benthamiana resulted in GalNAc O-glycosylation of co-expressed human O-glycoprotein substrates. A chimeric YFP construct containing a 3.5 tandem repeat sequence of MUC1 was glycosylated with up to three and five GalNAc residues when co-expressed with GalNAc-T2 and a combination of GalNAc-T2 and GalNAc-T4, respectively, as determined by mass spectrometry. O-Glycosylation was furthermore demonstrated on a tandem repeat of MUC16 and interferon α2b. In plants, prolines in certain classes of proteins are hydroxylated and further substituted with plant-specific O-glycosylation; unsubstituted hydroxyprolines were identified in our MUC1 construct. In summary, this study demonstrates that mammalian type O-glycosylation can be established in plants and that plants may serve as a host cell for production of recombinant O-glycoproteins with custom-designed O-glycosylation. The observed hydroxyproline modifications, however, call for additional future engineering efforts.

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“…Consequently, sTn antigen and relevant mucins that are aberrantly glycosylated with sTn have been extensively investigated for the immunotherapy of cancer (15)(16)(17)(18)(19)(20). The protein conjugates of sTn antigen could indeed elicit humoral immune response that showed remarkable specificity for cancer cells (21). The keyhole limpet hemocyanin (KLH) conjugate of sTn antigen (19,20) has been developed and tested as a therapeutic vaccine (Theratope ® ) for treatment of metastatic breast cancer (22,23).…”

Section: Introductionmentioning

confidence: 99%

Improving the Antigenicity of sTn Antigen by Modification of Its Sialic Acid Residue for Development of Glycoconjugate Cancer Vaccines

Guo

2006

Bioconjugate Chem.

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Sialyl Tn (sTn) antigen is a sialylated disaccharide abundantly expressed by many tumors. To search for effective cancer immunotherapies based on sTn antigen, this work designed and synthesized a series of unnatural N-acyl derivatives of sTn and studied their immunological property. For this purpose, an efficient method was developed to synthesize the natural and unnatural forms of sTn antigen and their protein conjugates. The resultant glycoconjugates were used to immunize C57BL/ 6 mice, and the immune response was assessed by ELISA. Whereas the keyhole limpet hemocyanin (KLH) conjugate of sTn elicited low levels of IgM antibodies, the KLH conjugates of N-iso-butanoyl sTn and N-phenylacetyl sTn, especially the latter, induced high titers of antigen-specific IgG antibodies, showing a T-cell dependent response which is critical for the antitumor activity. The results suggest that the modified forms of sTn, especially N-phenylacetyl sTn, have improved antigenicity and promising immunological properties for being used as cancer vaccines.

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Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance

Cited by 233 publications

References 46 publications

Microvesicle Cargo of Tumor-Associated MUC1 to Dendritic Cells Allows Cross-presentation and Specific Carbohydrate Processing

Microvesicle Cargo of Tumor-Associated MUC1 to Dendritic Cells Allows Cross-presentation and Specific Carbohydrate Processing

Engineering Mammalian Mucin-type O-Glycosylation in Plants

Improving the Antigenicity of sTn Antigen by Modification of Its Sialic Acid Residue for Development of Glycoconjugate Cancer Vaccines

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