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Enhanced major histocompatibility complex class i binding and immune responses through anchor modification of the non-canonical tumour-associated mucin 1-8 peptide

Academic Article
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Overview

authors

  • Lazoura, E.
  • Lodding, J.
  • Farrugia, W.
  • Ramsland, P. A.
  • Stevens, J.
  • Wilson, Ian
  • Pietersz, G. A.
  • Apostolopoulos, V.

publication date

  • November 2006

journal

  • Immunology  Journal

abstract

  • Designing peptide-based vaccines for therapeutic applications in cancer immunotherapy requires detailed knowledge of the interactions between the antigenic peptide and major histocompatibility complex (MHC) in addition to that between the peptide-MHC complex and the T-cell receptor. Past efforts to immunize with high-affinity tumour-associated antigenic peptides have not been very immunogenic, which may be attributed to the lack of T cells to these peptides, having been deleted during thymic development. For this reason, low-to-medium affinity non-canonical peptides represent more suitable candidates. However, in addition to the difficulty in identifying such antigens, peptide binding to MHC, and hence its ability to induce a strong immune response, is limited. Therefore, to enhance binding to MHC and improve immune responses, anchor modifications of non-canonical tumour-associated peptides would be advantageous. In this study, the non-canonical tumour-associated peptide from MUC1, MUC1-8 (SAPDTRPA), was modified at the MHC anchor residues to SAPDFRPL (MUC1-8-5F8L) and showed enhanced binding to H-2Kb and improved immune responses. Furthermore, the crystal structure of MUC1-8-5F8L in complex with H-2Kb was determined and it revealed that binding of the peptide to MHC is similar to that of the canonical peptide OVA8 (SIINFEKL).

subject areas

  • Animals
  • Antigens, Neoplasm
  • Cancer Vaccines
  • Cell Line
  • Crystallography, X-Ray
  • Drosophila melanogaster
  • H-2 Antigens
  • Histocompatibility Antigens Class I
  • Immunity, Cellular
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Mucin-1
  • Mutation
  • Peptide Fragments
  • Protein Binding
  • Structure-Activity Relationship
  • T-Lymphocyte Subsets
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Research

keywords

  • H-2K(b)
  • anchor modifications
  • mucin 1
  • mucin 1-8
  • non-canonical peptide
  • vaccine design
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Identity

PubMed Central ID

  • PMC1819580

International Standard Serial Number (ISSN)

  • 0019-2805

Digital Object Identifier (DOI)

  • 10.1111/j.1365-2567.2006.02434.x

PubMed ID

  • 17067310
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Additional Document Info

start page

  • 306

end page

  • 316

volume

  • 119

issue

  • 3

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