A general strategy to enhance immunogenicity of low-affinity HLA-A2. 1-associated peptides: implication in the identification of cryptic tumor epitopes.
Low-affinity MHC class I-associated cryptic epitopes derived from self proteins overexpressed in a wide variety of human tumors or derived from antigens of viruses exhibiting a high mutation rate, could be interesting candidates for tumor and virus immunotherapy, respectively. However, identification of low-affinity MHC-associated epitopes comes up against their poor immunogenicity. Here we describe an approach that enhances immunogenicity of nonimmunogenic low-affinity HLA-A2.1-binding peptides. It consists of modifying their sequence by introducing a tyrosine in the first position (P1Y). P1Y substitution enhances affinity of HLA-A2.1-associated peptides without altering their antigenic specificity. In fact, P1Y variants of ten nonimmunogenic low-affinity peptides exhibited a 2.3- to 55-fold higher binding affinity and/or stabilized the HLA-A2.1 for at least 2 h more than the corresponding native peptides. More importantly, P1Y variants efficiently triggered in vivo native peptide-specific CTL which also recognized the corresponding naturally processed epitope. The possibility for generating CTL against any low-affinity HLA-A2.1-associated peptide provides us with the necessary tool for the identification of cryptic tumor and virus epitopes which could be used for peptide-based immunotherapy.
Tourdot
S
S
INSERM 487, Villejuif, France.
Scardino
A
A
Saloustrou
E
E
Gross
D A
DA
Pascolo
S
S
Cordopatis
P
P
Lemonnier
F A
FA
Kosmatopoulos
K
K
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D000939:Epitopes; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D000939:Epitopes; D015789:HLA-A2 Antigen