title: A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen.
abstract: Human CD8(+) cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective. The melanocyte differentiation protein, glycoprotein 100 (gp100), encodes a naturally processed epitope that is an attractive target for melanoma immunotherapies, in particular peptide-based vaccines. Previous studies have shown that substitutions at peptide residue Glu(3) have a broad negative impact on polyclonal T-cell responses. Here, we describe the first atomic structure of a natural cognate TCR in complex with this gp100 epitope and highlight the relatively high affinity of the interaction. Alanine scan mutagenesis performed across the gp100(280-288) peptide showed that Glu(3) was critically important for TCR binding. Unexpectedly, structural analysis demonstrated that the Glu(3) → Ala substitution resulted in a molecular switch that was transmitted to adjacent residues, abrogating TCR binding and T-cell recognition. These findings help to clarify the mechanism of T-cell recognition of gp100 during melanoma responses and could direct the development of altered peptides for vaccination.
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Bulek
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Fuller
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Angharad
authors.initials: A
authors.lastname: Lloyd
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Meriem
authors.initials: M
authors.lastname: Attaf
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Garry
authors.initials: G
authors.lastname: Dolton
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom coledk@cf.ac.uk.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020836:Protein Structure, Quaternary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D058951:gp100 Melanoma Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen
keywords: CD8+ T-cells; T-cell receptor (TCR); X-ray crystallography; cancer; gp100; heteroclitic peptides; melanoma; peptide human leukocyte antigen (pHLA); surface plasmon resonance (SPR)