Immune Recognition of Tumor-Associated Mucin MUC1 is Achieved by a Fully Synthetic Aberrantly Glycosylated MUC1 Tripartite Vaccine
Open accessAbstract
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.
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“Thus, TACAs have been coupled with different compounds, including zwitterionic polysaccharide A1 (PSA1), Toll-like receptor 2 (TLR2) ligand, Pam3CysSerK4, and T-cell peptide epitopes, to develop self-adjuvant multi-component cancer vaccines [255].”
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- Authors
- Lakshminarayanan, V., Thompson, P., Wolfert, M. A., Buskas, T., Bradley, J. M., Pathangey, L. B., Madsen, C. S., Cohen, P. A., Gendler, S. J., & Boons, G.-J.
- Affiliations
- Mayo Clinic in Arizona (US)
- University of Georgia (US)
- Mayo Clinic (US)
- Departments of aBiochemistry and Molecular Biology and
- Corresponding author
- Lakshminarayanan, Vani
- Thompson, Pamela
- Madsen, Cathy S.
- Gendler, Sandra J.
- Boons, Geert-Jan
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-12-14
- Volume
- 109
- Issue
- 1
- Pages
- 261-266
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3252914
- OpenAlex
- W2082718424
- Cited by
- 301
- References
- 57
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 12 · 2023: 15 · 2022: 15 · 2021: 15 · 2020: 20 · 2019: 17 · 2018: 19 · 2017: 16 · 2016: 31 · 2015: 39 · 2014: 36 · 2013: 31 · 2012: 17
- FWCI
- 12.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Clinic (P50 CA116201, CA102701, CA116201, P50 CA102701)
- National Institutes of Health (CA11620 1, CA102701)
- National Cancer Institute (CA102701, R01CA088986, CA-116201, P50CA102701, R01 CA88986, P50CA116201)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Keywords
- MUC1, tumor-associated mucins, aberrant glycosylation, cytotoxic T lymphocytes, antibody-dependent cellular cytotoxicity, breast cancer, cancer immunotherapy, MHC binding, T-helper epitopes
- MeSH terms
- Amino Acid Sequence, Animals, Antibody-Dependent Cell Cytotoxicity, Antigens, Neoplasm, Enzyme-Linked Immunosorbent Assay, Glycosylation, Humans, Immunity, Cellular, Mammary Tumor Virus, Mouse, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Neoplasms, T-Lymphocytes, Cytotoxic, Vaccines, Synthetic, Cytokines, Mucin-1, Cancer Vaccines, Tumor Burden, Mice, Immunity, Humoral
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