A glycopeptide in complex with MHC class I uses the GalNAc residue as an anchor

Apostolopoulos, Vasso; Yuriev, Elizabeth; Ramsland, Paul A.; Halton, Jodie; Osinski, Carla; Li, Wenjun; Plebanski, Magdalena; Paulsen, Hans

doi:10.1073/pnas.2432220100

Cited by 90 publications

(89 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previously, the MUC1-derived glycopeptide SAPDTαGalNAc)RPAP, was identified as the antigenic-dominant domain of the tandem repeat of MUC1 (8,9). Furthermore, this epitope can also be presented in complex with MHC class I (K b ) resulting in the activation of CTLs (38). The MHC class II restricted T helper epitope of 1 was expected to induce a class switch from IgM to IgG antibody production and facilitate the presentation of exogenous glycopeptides on MHC class 1.…”

Section: Resultsmentioning

confidence: 99%

“…It is known that short Olinked glycans such as the Tn and STn on MUC1 tandem repeats remain intact during DC processing in the MHC class I and II pathways (14-17, 51, 52) and thus it is possible to elicit glycopeptide selective CTL responses. Moreover, there is evidence that MUC1 glycopeptides can bind more strongly to the MHC class I mouse allele H-2K b compared with the corresponding unglycosylated peptide (38). The progression of carcinomas is not only associated with the modification of MUC1 with truncated saccharides such as the Tn antigen but these structures are present at much higher densities and thus effective immunotherapy needs to elicit responses that are directed to such structures.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

Lakshminarayanan¹,

Thompson

Wolfert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

278

260

View full text Add to dashboard Cite

The mucin MUC1 is typically aberrantly glycosylated by epithelial cancer cells manifested by truncated O-linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and are susceptible to recognition by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Efforts to elicit CTLs and IgG antibodies against cancer-expressed MUC1 have not been successful when nonglycosylated MUC1 sequences were used for vaccination, probably due to conformational dissimilarities. Immunizations with densely glycosylated MUC1 peptides have also been ineffective due to impaired susceptibility to antigen processing. Given the challenges to immuno-target tumor-associated MUC1, we have identified the minimum requirements to consistently induce CTLs and ADCC-mediating antibodies specific for the tumor form of MUC1 resulting in a therapeutic response in a mouse model of mammary cancer. The vaccine is composed of the immunoadjuvant Pam 3 CysSK 4 , a peptide T helper epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three components was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs which recognized only nonglycosylated peptide. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control. As a result, immunization with the glycosylated tripartite vaccine was superior in tumor prevention. Besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.cancer vaccine | multicomponent | chemical synthesis | Tn antigen

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

Lakshminarayanan¹,

Thompson

Wolfert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

278

260

View full text Add to dashboard Cite

show abstract

“…Future studies will focus on generating glycosylated and/or anchor-improved MUC1 peptides that will have higher MHC binding and thus greater ability to activate T cells [65]. The idea that the glycopeptides from highly glycosylated proteins can serve as CTL-based vaccines has been pioneered by Olivera Finn [66], Vasso Apostolopoulos [67] and Alexandra Franco [52,64] and colleagues. Eliciting immunity to the novel anchor-modified glycosylated MUC1 peptides may result in robust anti-tumor immunity and long-term immune memory.…”

Section: Discussionmentioning

confidence: 99%

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

Mukherjee

Pathangey

Bradley

et al. 2007

Vaccine

View full text Add to dashboard Cite

A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan helper peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust antitumor response. The vaccine stimulated IFN-γ-producing CD4 + helper and CD8 + cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

show abstract

“…It is reasonable to think that in vivo glycoepitopes displayed by the tumor-associated glycoforms are targets for the antitumor response. In fact, the significant IgG immune response in patients with cancer was shown to be directed against the MUC1 glycoepitopes (5), and the binding of the MUC1 glycopeptides to the MHC groove could induce T-cell activation in mouse models and in human studies in vitro (6)(7)(8).…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

A glycopeptide in complex with MHC class I uses the GalNAc residue as an anchor

Cited by 90 publications

References 40 publications

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

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

Contact Info

Product

Resources

About