Aberrant glycosylation of anchor-optimized MUC1 peptides can enhance antigen binding affinity and reverse tolerance to cytotoxic T lymphocytes

Latha B. Pathangey, Vani Lakshminarayanan, Vera Jean Suman, Barbara A Pockaj, Pinku Mukherjee, Sandra J Gendler

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article number31
JournalBiomolecules
Volume6
Issue number3
DOIs
StatePublished - Sep 1 2016

Fingerprint

Glycosylation
T-cells
Cytotoxic T-Lymphocytes
Anchors
Antigens
Peptides
Vaccines
Breast Neoplasms
Tumors
Cancer Vaccines
Tandem Repeat Sequences
Autoantigens
Epitopes
Neoplasms
Cells
Tissue Donors
Clinical Trials

Keywords

  • Breast cancer
  • CTL
  • Heteroclitic antigen
  • Immunotherapy
  • Mucin1
  • Tn antigen
  • Vaccine

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry
  • Molecular Biology

Cite this

Aberrant glycosylation of anchor-optimized MUC1 peptides can enhance antigen binding affinity and reverse tolerance to cytotoxic T lymphocytes. / Pathangey, Latha B.; Lakshminarayanan, Vani; Suman, Vera Jean; Pockaj, Barbara A; Mukherjee, Pinku; Gendler, Sandra J.

In: Biomolecules, Vol. 6, No. 3, 31, 01.09.2016.

Research output: Contribution to journalArticle

@article{39ac2c77a2ba4229910c1ded58eb13e5,
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.",
keywords = "Breast cancer, CTL, Heteroclitic antigen, Immunotherapy, Mucin1, Tn antigen, Vaccine",
author = "Pathangey, {Latha B.} and Vani Lakshminarayanan and Suman, {Vera Jean} and Pockaj, {Barbara A} and Pinku Mukherjee and Gendler, {Sandra J}",
year = "2016",
month = "9",
day = "1",
doi = "10.3390/biom6030031",
language = "English (US)",
volume = "6",
journal = "Biomolecules",
issn = "2218-273X",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "3",

}

TY - JOUR

T1 - Aberrant glycosylation of anchor-optimized MUC1 peptides can enhance antigen binding affinity and reverse tolerance to cytotoxic T lymphocytes

AU - Pathangey, Latha B.

AU - Lakshminarayanan, Vani

AU - Suman, Vera Jean

AU - Pockaj, Barbara A

AU - Mukherjee, Pinku

AU - Gendler, Sandra J

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

KW - Breast cancer

KW - CTL

KW - Heteroclitic antigen

KW - Immunotherapy

KW - Mucin1

KW - Tn antigen

KW - Vaccine

UR - http://www.scopus.com/inward/record.url?scp=85012048838&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85012048838&partnerID=8YFLogxK

U2 - 10.3390/biom6030031

DO - 10.3390/biom6030031

M3 - Article

C2 - 27367740

AN - SCOPUS:85012048838

VL - 6

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 3

M1 - 31

ER -