title: Vaccination with a Melan-A peptide selects an oligoclonal T cell population with increased functional avidity and tumor reactivity.
abstract: Both the underlying molecular mechanisms and the kinetics of TCR repertoire selection following vaccination against tumor Ags in humans have remained largely unexplored. To gain insight into these questions, we performed a functional and structural longitudinal analysis of the TCR of circulating CD8(+) T cells specific for the HLA-A2-restricted immunodominant epitope from the melanocyte differentiation Ag Melan-A in a melanoma patient who developed a vigorous and sustained Ag-specific T cell response following vaccination with the corresponding synthetic peptide. We observed an increase in functional avidity of Ag recognition and in tumor reactivity in the postimmune Melan-A-specific populations as compared with the preimmune blood sample. Improved Ag recognition correlated with an increase in the t(1/2) of peptide/MHC interaction with the TCR as assessed by kinetic analysis of A2/Melan-A peptide multimer staining decay. Ex vivo analysis of the clonal composition of Melan-A-specific CD8(+) T cells at different time points during vaccination revealed that the response was the result of asynchronous expansion of several distinct T cell clones. Some of these T cell clones were also identified at a metastatic tumor site. Collectively, these data show that tumor peptide-driven immune stimulation leads to the selection of high-avidity T cell clones of increased tumor reactivity that independently evolve within oligoclonal populations.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, and Multidisciplinary Oncology Center, University Hospital, Lausanne, Switzerland. danila.valmori@inst.hospvd.ch
authors.forename: Danila
authors.initials: D
authors.lastname: Valmori
authors.forename: Valerie
authors.initials: V
authors.lastname: Dutoit
authors.forename: Valerie
authors.initials: V
authors.lastname: Schnuriger
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Quiquerez
authors.forename: Mikaël J
authors.initials: MJ
authors.lastname: Pittet
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Verena
authors.initials: V
authors.lastname: Rubio-Godoy
authors.forename: Paul R
authors.initials: PR
authors.lastname: Walker
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.forename: Danielle
authors.initials: D
authors.lastname: Liénard
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Cerottini
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000096:biosynthesis / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D019674:Genes, T-Cell Receptor beta; D015789:HLA-A2 Antigen / Q000096:biosynthesis; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D016130:Immunophenotyping; D008137:Longitudinal Studies; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D022801:Complementarity Determining Regions; D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D007135:Immunoglobulin Variable Region; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments