Design of agonistic altered peptides for the robust induction of CTL directed towards H-2Db in complex with the melanoma-associated epitope gp100.
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-2D(b) 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.
van Stipdonk
Marianne J B
MJ
Departments of Immunohematology and Blood transfusion and Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
Badia-Martinez
Daniel
D
Sluijter
Marjolein
M
Offringa
Rienk
R
van Hall
Thorbald
T
Achour
Adnane
A
D000595:Amino Acid Sequence; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D011487:Protein Conformation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D058951:gp100 Melanoma Antigen
D019496:Cancer Vaccines; D000939:Epitopes; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen