title: Structural and kinetic basis for heightened immunogenicity of T cell vaccines.
abstract: Analogue peptides with enhanced binding affinity to major histocompatibility class (MHC) I molecules are currently being used in cancer patients to elicit stronger T cell responses. However, it remains unclear as to how alterations of anchor residues may affect T cell receptor (TCR) recognition. We correlate functional, thermodynamic, and structural parameters of TCR-peptide-MHC binding and demonstrate the effect of anchor residue modifications of the human histocompatibility leukocyte antigens (HLA)-A2 tumor epitope NY-ESO-1(157-165)-SLLMWITQC on TCR recognition. The crystal structure of the wild-type peptide complexed with a specific TCR shows that TCR binding centers on two prominent, sequential, peptide sidechains, methionine-tryptophan. Cysteine-to-valine substitution at peptide position 9, while optimizing peptide binding to the MHC, repositions the peptide main chain and generates subtly enhanced interactions between the analogue peptide and the TCR. Binding analyses confirm tighter binding of the analogue peptide to HLA-A2 and improved soluble TCR binding. Recognition of analogue peptide stimulates faster polarization of lytic granules to the immunological synapse, reduces dependence on CD8 binding, and induces greater numbers of cross-reactive cytotoxic T lymphocyte to SLLMWITQC. These results provide important insights into heightened immunogenicity of analogue peptides and highlight the importance of incorporating structural data into the process of rational optimization of superagonist peptides for clinical trials.
authors.affiliation: Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Ji-Li
authors.initials: JL
authors.lastname: Chen
authors.forename: Guillaume
authors.initials: G
authors.lastname: Stewart-Jones
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bossi
authors.forename: Nikolai M
authors.initials: NM
authors.lastname: Lissin
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: Ed Man Lik
authors.initials: EM
authors.lastname: Choi
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.forename: P Rod
authors.initials: PR
authors.lastname: Dunbar
authors.forename: Robert M
authors.initials: RM
authors.lastname: Esnouf
authors.forename: Malkit
authors.initials: M
authors.lastname: Sami
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Boulter
authors.forename: Pierre
authors.initials: P
authors.lastname: Rizkallah
authors.forename: Christoph
authors.initials: C
authors.lastname: Renner
authors.forename: Andrew
authors.initials: A
authors.lastname: Sewell
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.forename: Gillian
authors.initials: G
authors.lastname: Griffiths
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000276:immunology; D019496:Cancer Vaccines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054407:Chemokine CCL4; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology; D007114:Immunization; D007371:Interferon-gamma / Q000032:analysis; D019402:Macrophage Inflammatory Proteins / Q000032:analysis; D008285:Major Histocompatibility Complex / Q000276:immunology; D008565:Membrane Proteins / Q000737:chemistry* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014614:Vaccines, Synthetic / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D054407:Chemokine CCL4; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014614:Vaccines, Synthetic; D007371:Interferon-gamma