title: Aberrant Glycosylation of Anchor-Optimized MUC1 Peptides Can Enhance Antigen Binding Affinity and Reverse Tolerance to Cytotoxic T Lymphocytes.
abstract: Cancer vaccines have often failed to live up to their promise, although recent results with checkpoint inhibitors are reviving hopes that they will soon fulfill their promise. Although mutation-specific vaccines are under development, there is still high interest in an off-the-shelf vaccine to a ubiquitous antigen, such as MUC1, which is aberrantly expressed on most solid and many hematological tumors, including more than 90% of breast carcinomas. Clinical trials for MUC1 have shown variable success, likely because of immunological tolerance to a self-antigen and to poor immunogenicity of tandem repeat peptides. We hypothesized that MUC1 peptides could be optimized, relying on heteroclitic optimizations of potential anchor amino acids with and without tumor-specific glycosylation of the peptides. We have identified novel MUC1 class I peptides that bind to HLA-A*0201 molecules with significantly higher affinity and function than the native MUC1 peptides. These peptides elicited CTLs from normal donors, as well as breast cancer patients, which were highly effective in killing MUC1-expressing MCF-7 breast cancer cells. Each peptide elicited lytic responses in greater than 6/8 of normal individuals and 3/3 breast cancer patients. The CTLs generated against the glycosylated-anchor modified peptides cross reacted with the native MUC1 peptide, STAPPVHNV, suggesting these analog peptides may offer substantial improvement in the design of epitope-based vaccines.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic in Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA. pathangey.latha@mayo.edu.|Department of Immunology, College of Medicine, Mayo Clinic in Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA. pathangey.latha@mayo.edu.
authors.forename: Latha B
authors.initials: LB
authors.lastname: Pathangey
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic in Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA. lakshminarayanan.vani@gmail.com.|Department of Immunology, College of Medicine, Mayo Clinic in Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA. lakshminarayanan.vani@gmail.com.
authors.forename: Vani
authors.initials: V
authors.lastname: Lakshminarayanan
authors.affiliation: Cancer Center Statistics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. suman.vera@mayo.edu.
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.affiliation: Department of Surgery, Mayo Clinic in Arizona, Mayo Clinic Hospital, 5777 E. Mayo Boulevard, Phoenix, AZ 85054, USA. pockaj.barbara@mayo.edu.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Pockaj
authors.affiliation: Department of Immunology, College of Medicine, Mayo Clinic in Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA. pmukherj@uncc.edu.
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic in Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA. gendler.sandra@mayo.edu.|Department of Immunology, College of Medicine, Mayo Clinic in Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA. gendler.sandra@mayo.edu.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines; D005260:Female; D006031:Glycosylation; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma; D061986:MCF-7 Cells; D008875:Middle Aged; D018396:Mucin-1 / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C060192:MUC1 protein, human; D018396:Mucin-1; D010455:Peptides; D007371:Interferon-gamma
keywords: CTL; Mucin1; Tn antigen; breast cancer; heteroclitic antigen; immunotherapy; vaccine