Design of agonistic altered peptides for the robust induction of CTL directed towards H-2Db in complex with the melanoma-associated epitope gp100
| Autor: | Thorbald van Hall, Marjolein Sluijter, Daniel Badia-Martinez, Marianne J. B. van Stipdonk, Adnane Achour, Rienk Offringa |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Models Molecular Cancer Research Protein Conformation Molecular Sequence Data chemical and pharmacologic phenomena Peptide Major histocompatibility complex complex mixtures Cancer Vaccines Epitope Epitopes Mice Antigen MHC class I Animals Amino Acid Sequence Histocompatibility Antigen H-2D chemistry.chemical_classification Membrane Glycoproteins biology Mimotope Immunogenicity H-2 Antigens Neoplasms Experimental Peptide Fragments Mice Inbred C57BL CTL Oncology Biochemistry chemistry Immunology biology.protein T-Lymphocytes Cytotoxic gp100 Melanoma Antigen |
| Zdroj: | Cancer research. 69(19) |
| ISSN: | 1538-7445 |
| Popis: | Immunogenicity of tumor-associated antigens (TAA) is often weak because many TAA are autoantigens for which the T-cell repertoire is sculpted by tolerance mechanisms. Substitutions at main anchor positions to increase the complementarity between the peptide and the MHC class I (MHC-I) binding cleft constitute a common procedure to improve binding capacity and immunogenicity of TAA. However, such alterations are tailored for each MHC-I allele and may recruit different CTL specificities through conformational changes in the targeted peptides. Comparative analysis of substituted melanoma-differentiation antigen gp100 in complex with H-2Db revealed that combined introduction of glycine and proline residues at the nonanchor positions 2 and 3, respectively, resulted in an agonistic altered peptide with dramatically enhanced binding affinity, stability, and immunogenicity of this TAA. Peptide vaccination using the p2Gp3P-altered peptide version of gp100 induced high frequencies of melanoma-specific CTL in the endogenous CD8+ repertoire. Crystal structure analysis of MHC/peptide complexes revealed that the conformation of the modified p2Gp3P-peptide was similar to the wild-type peptide, and indicated that this mimotope was stabilized through interactions between peptide residue p3P and the tyrosine residue Y159 that is conserved among most known MHC-I molecules throughout mammalian species. Our results may provide an alternative approach to enhance MHC stabilization capacity and immunogenicity of low-affinity peptides for induction of robust tumor-specific CTL. [Cancer Res 2009;69(19):7784–92] |
| Databáze: | OpenAIRE |
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