title: Cytotoxic T lymphocytes directed against a tumor-specific mutated antigen display similar HLA tetramer binding but distinct functional avidity and tissue distribution.
abstract: We have previously identified an antigen (Ag) recognized on a human large cell carcinoma of the lung by a tumor-specific cytotoxic T lymphocyte clone derived from autologous tumor infiltrating lymphocytes (TILs). The antigenic peptide is presented by HLA-A2 molecules and is encoded by a mutated alpha-actinin-4 (ACTN4) gene. In the present report, we have isolated two anti-alpha-actinin-4 T cell clones from the same patient TIL and from his peripheral blood lymphocytes (PBLs) by using tetramers of soluble HLA-A2 molecules loaded with the mutated peptide. Although all of the clones displayed similar tetramer labeling, those isolated from PBL showed lower avidity of Ag recognition and killed the specific target much less efficiently, indicating that tetramer staining does not correlate with clone avidity/tumor reactivity. T cell receptor (TCR) analysis revealed that alpha-actinin-4-reactive clones used distinct alpha and beta chain rearrangements, demonstrating TCR repertoire diversity. Interestingly, TCR beta chain gene usage indicated that only Ag-specific clones with high functional avidity were expanded at the tumor site, whereas a low-avidity clone was exclusively amplified in patient peripheral blood. Our results point to the existence of distinct but overlapping antitumor TCR repertoires in TIL and PBL and suggest a selective in situ expansion of tumor-specific cytotoxic T lymphocyte with high avidity/tumor reactivity.
authors.affiliation: Laboratoire Cytokines et Immunologie des Tumeurs Humaines, U487 Institut National de la Santé et de la Recherche Médicale, Institut Gustave Roussy, Institut Fédératif de Recherche-54, F-94805 Villejuif, Cedex, France.
authors.forename: Hamid
authors.initials: H
authors.lastname: Echchakir
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dorothée
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vergnon
authors.forename: Jeanne
authors.initials: J
authors.lastname: Menez
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D018287:Carcinoma, Large Cell / Q000276:immunology; D002460:Cell Line; D022801:Complementarity Determining Regions / Q000235:genetics; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008840:Microfilament Proteins; D009154:Mutation; D020836:Protein Structure, Quaternary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014018:Tissue Distribution
chemical_list: C111453:ACTN4 protein, human; D000951:Antigens, Neoplasm; D022801:Complementarity Determining Regions; D015789:HLA-A2 Antigen; D008840:Microfilament Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000185:Actinin