title: A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: spontaneous priming and efficient boosting by vaccination.
abstract: Despite major progress in T lymphocyte analysis in melanoma patients, TCR repertoire selection and kinetics in response to tumor Ags remain largely unexplored. In this study, using a novel ex vivo molecular-based approach at the single-cell level, we identified a single, naturally primed T cell clone that dominated the human CD8(+) T cell response to the Melan-A/MART-1 Ag. The dominant clone expressed a high-avidity TCR to cognate tumor Ag, efficiently killed tumor cells, and prevailed in the differentiated effector-memory T lymphocyte compartment. TCR sequencing also revealed that this particular clone arose at least 1 year before vaccination, displayed long-term persistence, and efficient homing to metastases. Remarkably, during concomitant vaccination over 3.5 years, the frequency of the pre-existing clone progressively increased, reaching up to 2.5% of the circulating CD8 pool while its effector functions were enhanced. In parallel, the disease stabilized, but subsequently progressed with loss of Melan-A expression by melanoma cells. Collectively, combined ex vivo analysis of T cell differentiation and clonality revealed for the first time a strong expansion of a tumor Ag-specific human T cell clone, comparable to protective virus-specific T cells. The observed successful boosting by peptide vaccination support further development of immunotherapy by including strategies to overcome immune escape.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.forename: Petra
authors.initials: P
authors.lastname: Baumgaertner
authors.forename: Catherine
authors.initials: C
authors.lastname: Barbey
authors.forename: Verena
authors.initials: V
authors.lastname: Rubio-Godoy
authors.forename: Alexandre
authors.initials: A
authors.lastname: Moulin
authors.forename: Patricia
authors.initials: P
authors.lastname: Corthesy
authors.forename: Estelle
authors.initials: E
authors.lastname: Devevre
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
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: Nathalie
authors.initials: N
authors.lastname: Rufer
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000097:blood / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology; D008207:Lymphatic Metastasis / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D009363:Neoplasm Proteins / Q000097:blood / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000097:blood / Q000378:metabolism; D013997:Time Factors; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D022223:Vaccines, Subunit